Diaryl substituted pyridinones

ABSTRACT

Disclosed are compounds Formula I 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 /R 4 , and R 5  are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/367,987, filed Feb. 14, 2003, now U.S. Pat. No. 7,067,540, whichclaims priority from U.S. Provisional Application Ser. No. 60/357,029,filed Feb. 14, 2002, and U.S. Provisional Application Ser. No.60/436,915, filed Dec. 30, 2002, all of which are incorporated herein byreference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The instant invention relates to substituted pyridinones that are usefulfor treating diseases and conditions caused or exacerbated byunregulated p38 MAP kinase activity. Pharmaceutical compositionscontaining the pyridinone compounds, methods of preparing the pyridonecompounds and methods of treatment using the compounds are alsodisclosed.

2. Description of the Related Art

Numerous cell surface receptors use one or more of the mitogen-activatedprotein kinase (MAP kinase) cascades during signal transduction. MAPkinases are a family of protein-directed serine/threonine kinases thatare activated by dual phosphorylation. One subgroup of the MAP kinasesis p38 MAP kinase, which is activated by a variety of signals includingproinflammatory cytokines such as tumor necrosis factor (TNF) andinterleukin-1 (IL-1), as well as bacterial lipopolysaccharides andenvironmental stress such as osmotic shock and ultraviolet radiation(Ono, K. and J. Han, Cell Signal. 12: 1, 2000). Within the p38 kinasefamily, there are four distinct isozymes: p38 alpha, p38 beta, p38gamma, and p38 delta. The p38 kinase family function downstream of anactivating stimulus by phosphorylating and activating transcriptionfactors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g.MAPKAP-2 and MAPKAP-3) (Trends in Cell biology 7, 353-361, 1997;Mol CellBiology 19, 21-30, 1999; EMBO J=20, 466-479, 2001). Upon activation, thep38 kinase cascade leads to the induction of gene expression of severalfactors involved in inflammation and immunity including TNF,interleukin-6, granulocyte-macrophage colony stimulating factor(GM-CSF), and HIV long terminal repeat (Paul et al., Cell Signal. 9:403-410, 1997). The products of the p38 phosphorylation stimulate theproduction of inflammatory cytokines and other proteins, including TNFand IL-1, and cyclooxygenase-2, and also possibly modulate the effectsof these cytokines on their target cells, and thus stimulateinflammation processes (Lee, J. C. et al, Nature, 372: 376, 1994).

P38 MAP kinases have also been shown to promote apoptosis duringischemia in cardiac myocytes, which suggests that p38 MAP kinaseinhibitors can be used to treat ischemic heart disease (J. Biol. Chem.274, 6272, 1999). They are also required for T-cell HIV-1 replicationand may be useful targets for AIDS therapy. P38 pathway inhibitors havebeen used to increase cancer cell sensitivity to cancer therapy alsofind use in the treatment of asthma (JPET 293, 281, 2000).

TNF is a cytokine and a potent proinflammatory mediator implicated ininflammatory conditions such as arthritis, asthma, septic shock,non-insulin dependent diabetes mellitus, multiple sclerosis, asthma, andinflammatory bowel disease. Thus inhibitors of p38 MAP kinases (requiredfor TNF production) may be useful for the treatment of inflammatoryconditions resulting from excessive cytokine production such asarthritis. (Boehm, J. C. and J. L. Adams, Exp. Opin. Ther. Patents 10:25, 2000, and references cited therein). TNF has also been implicated inviral infections, such as HIV, influenza virus, and herpes virusincluding herpes simplex virus type-1 (HSV-1), herpes simplex virustype-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis,among others.

Excessive or unregulated TNF production has also been shown to produceelevated levels of IL-1. Inhibition of TNF, therefore, should reducelevels of IL-1 (European Cytokine Netw 6, 225, 1995) and amelioratedisease states caused by unregulated IL-1 synthesis. Such disease statesinclude rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis, sepsis, septic shock, endotoxic shock, gram negativesepsis, toxic shock syndrome, adult respiratory distress syndrome,cerebral malaria, chronic pulmonary inflammatory disease, silicosis,pulmonary sarcosis, bone resorption diseases, reperfusion injury, graftversus host reaction, alallograft rejections, fever and myalgias due toinfection, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS relatedcomplex (ARC), keloid formation, scar tissue formation, Crohn's disease,ulcerative colitis, and pyresis.

IL-1 has also been shown to mediate a variety of biological activitiessuch as the activation of T-helper cells, induction of fever,stimulation of prostaglandin or collagenase production, neutrophilchemotaxis, and the suppression of plasma iron levels (Rev. Infect.Disease, 6, 51 (1984)). Elevated levels of IL-1 have also beenimplicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis,gouty arthritis, inflammatory bowel disease, adult respiratory distresssyndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis,anaphylaxis, muscle degeneration, cachexia, Reiter's syndrome, type Iand type II diabetes, bone resorption diseases, ischemia reperfusioninjury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis,septic shock, and toxic shock syndrome. Viruses sensitive to TNFinhibition, such as HIV-1, HIV-2, HIV-3, are also affected by IL-1production. In rheumatoid arthritis, both IL-1 and TNF inducecollagenase synthesis and ultimately lead to tissue destruction withinarthritic joints (Lymphokine Cytokine Res. (11): 253-256, (1992) andClin. Exp. Immunol. 989:244-250, (1992)).

IL-6 is another pro-inflammatory cytokine, which is associated with manyconditions including inflammation. Consequently, TNF, IL-1 and IL-6affect a wide variety of cells and tissues and are importantinflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines by inhibition ormodulation of p38 kinase is of benefit in controlling, reducing andalleviating many of these disease states and conditions. Therefore, thepresent invention concerns finding small molecule inhibitors ormodulators of p38 kinase and the p38 kinase pathway.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides compounds of Formula I(Embodiment I):

and pharmaceutically acceptable salts thereof, wherein

-   R₁ is H, halogen, NO₂, alkyl, carboxaldehyde, hydroxyalkyl,    dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl,    arylalkynyl, —CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl,    haloalkoxy, carboxyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂R;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy,        alkoxyalkyl and arylalkanoyl groups is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, or C₃-C₇        cycloalkyl;-   R₂ is H, OH, halogen, —OSO₂—(C₁-C₆)alkyl, —OSO₂-aryl, arylalkoxy,    aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy,    aryloxy(C₁-C₆)alkyl, alkyl, alkynyl, —OC(O)NH(CH₂)_(n)aryl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, alkoxyalkoxy, dialkylamino, alkyl,    alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl,    heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR₈R₉,    dialkylamino, or CO₂R, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of which groups is unsubstituted or substituted with 1, 2,        3, 4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, haloalkyl, heteroaryl,        heteroarylalkyl, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇,        —(C₁-C₄)alkyl C(O)NR₆R₇, —(C₁-C₄ alkyl)-NRC(O)NR₁₆R₁₇,        haloalkoxy, alkyl, CN, hydroxyalkyl, dihydroxyalkyl, alkoxy,        alkoxycarbonyl, phenyl, —SO₂-phenyl wherein the phenyl and        —SO₂-phenyl groups are optionally substituted with 1, 2, or 3        groups that are independently halogen or NO₂, or —OC(O)NR₆R₇,        wherein R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇ and the nitrogen to which they are attached form a        morpholinyl ring;    -   R₆ and R₇ are independently at each occurrence H, alkyl,        hydroxyalkyl, dihydroxyalkyl, alkoxy, alkanoyl, arylalkyl,        arylalkoxy, alkoxycarbonyl, —SO₂-alkyl, OH, alkoxy, alkoxyalkyl,        arylalkoxycarbonyl, —(C₁-C₄)alkyl-CO₂-alkyl, heteroarylalkyl, or        arylalkanoyl, wherein each is unsubstituted or substituted with        1, 2, or 3 groups that are independently, halogen, OH, SH,        heterocycloalkyl, heterocycloalkylalkyl, C₃-C₇ cycloalkyl,        alkoxy, NH₂, NH(alkyl), N(alkyl)(alkyl), —O-alkanoyl, alkyl,        haloalkyl, carboxaldehyde, or haloalkoxy; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl        S-oxide, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl,        or piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, alkoxycarbonyl, C₁-C₄        alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen;    -   R at each occurrence is independently hydrogen or C₁-C₆ alkyl        optionally substituted with 1 or 2 groups that are independently        OH, SH, halogen, amino, monoalkylamino, dialkylamino or C₃-C₆        cycloalkyl;    -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups        that are independently OH, SH, halogen, amino, monoalkylamino,        dialkylamino or C₃-C₆ cycloalkyl;    -   each R₈ is independently hydrogen, alkyl, alkanoyl, arylalkyl        and arylalkanoyl, wherein each of the above is optionally        substituted with 1, 2, 3, 4, or 5 groups that are independently        alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl;    -   each R₉ is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl,        cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl,        monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl,        —SO₂-phenyl, and aryl wherein each of the above is optionally        substituted with 1, 2, 3, 4, or 5 groups that are independently        alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl;-   R₃ is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl,    aryloxycarbonyl, arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,    —OC(O)N(alkyl)(CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,    arylthioalkoxy, alkenyl, —NR₆R₇, NR₆R₇—(C₁-C₆)alkyl, or alkyl,    wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,        —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is        unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that        are independently, halogen, alkoxy, alkyl, haloalkyl, or        haloalkoxy,    -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is hydrogen or R₄ is alkyl unsubstituted or substituted with one    or two groups that are independently CO₂R, —CO₂—(C₁-C₆)alkyl,    —C(O)NR₆R₇, —C(O)R₆, —N(R₃₀)C(O)NR₁₆R₁₇, —N(R₃₀)C(O)—(C₁-C₆)alkoxy,    or —NR₆R₇, arylalkoxy, arylalkyl, heteroaryl, heteroarylalkyl,    hydroxyalkyl, dihydroxyalkyl, haloalkyl, R₆R₇N—(C₁-C₆ alkyl)-,    —NR₆R₇, alkoxy, carboxaldehyde, —C(O)NR₆R₇, CO₂R, alkoxyalkyl, or    alkoxyalkoxy, wherein the heteroaryl or aryl portions of is the    above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, hydroxy, alkoxy, alkyl,    —CO₂—(C₁-C₆)alkyl, —CONR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆)alkyl-, nitro,    haloalkyl, or haloalkoxy; and-   R₅ is H, aryl, arylalkyl, arylthioalkyl, alkyl optionally    substituted with 1, 2, or 3 groups that are independently    arylalkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉, alkoxycarbonyl,    C₃-C₇ cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally    substituted with one trimethylsilyl group, amino, alkoxycarbonyl,    hydroxyalkyl, dihydroxyalkyl, alkynyl, —SO₂-alkyl, alkoxy optionally    substituted with one trimethylsilyl group, heterocycloalkylalkyl,    cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-SO₂-aryl,    heteroarylalkyl, heterocycloalkyl, heteroaryl, or alkenyl optionally    substituted with alkoxycarbonyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy,        alkoxycarbonyl, arylalkoxycarbonyl, CO₂R, CN, OH, hydroxyalkyl,        dihydroxyalkyl, amidinooxime, —NR₆R₇, —NR₈R₉, R₆R₇N—(C₁-C₆        alkyl)-, carboxaldehyde, SO₂alkyl, SO₂H, —SO₂NR₆R₇, alkanoyl        wherein the alkyl portion is optionally substituted with OH,        halogen or alkoxy, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,        amidino, haloalkyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄        alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O, —O—CH₂CH₂—O—, or haloalkoxy;        wherein        -   R₁₅ is H or C₁-C₆ alkyl; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

The invention also includes the intermediates that are useful in makingthe compounds of the invention.

These compounds bind and/or interact with p38 kinase and/or TNF.Preferably, they inhibit the activity of p38 kinase and/or TNF. They aretherefore used in treating p38 map kinase or TNF mediated disorders.Preferably they are used in treating p38 alpha or TNF mediateddisorders.

The instant invention also includes pharmaceutical compositionscomprising at least one compound of formula I and at least onepharmaceutically acceptable carrier, solvent, adjuvant or excipient.

The instant invention also includes methods of treating a TNF mediateddisorder, a p38 kinase mediated disorder, inflammation and/or arthritisin a subject, the method comprising treating a subject having orsusceptible to such disorder or condition with atherapeutically-effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred aspect, the invention provides compounds of formula Iwherein:

-   when R₂ is benzyloxy, R₃ is H, R₄ is H, and R₅ is benzyl or methyl,    R₁ is not hydrogen;-   no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen;    R₆ and R₇ are not simultaneously OH;-   when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ is not acetyl; and    R₄ and R₅ are not simultaneously hydrogen.

Embodiment 2

Compounds of the formula:

and the pharmaceutically acceptable salts thereof, wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,    dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl,    arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, carboxyl,    or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂R;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy,        alkoxyalkyl and arylalkanoyl groups is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, or cyclopropyl;-   R₂ is H, OH, halogen, —OSO₂—(C₁-C₆)alkyl, —OSO₂-aryl, arylalkoxy,    aryloxy, arylthioalkoxy, arylalkynyl, alkoxy, phenyloxy(C₁-C₆)alkyl,    —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl)(CH₂)_(n)aryl, alkyl, alkynyl,    alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl,    aryloxyalkyl, or CO₂R, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, —NR₆R₇,        haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl,        —(C₁-C₄)alkyl-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇,        (C₁-C₄ alkyl)-NRC(O)NR₁₆R₁₇, CN, hydroxyalkyl, dihydroxyalkyl,        —OC(O)NR₆R₇, or (C₁-C₆)alkyl-N(R)—CO₂R₃₀, wherein        -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or        -   R₁₆, R₁₇ and the nitrogen to which they are attached form a            morpholinyl ring;        -   R₆ and R₇ are independently at each occurrence H, alkyl,            hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl,            arylalkyl, arylalkoxy, arylalkoxycarbonyl, or arylalkanoyl,            wherein each of the above is unsubstituted or substituted            with 1, 2, or 3 groups that are independently, halogen,            alkoxy, alkyl, OH, SH, carboxaldehyde, haloalkyl, or            haloalkoxy; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,            thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, alkoxycarbonyl,            hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen;    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   R at each occurrence is independently H or C₁-C₆ alkyl        optionally substituted with 1 or 2 groups that are independently        OH, SH, halogen, amino, monoalkylamino, dialkylamino or C₃-C₆        cycloalkyl;    -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups        that are independently OH, SH, halogen, amino, monoalkylamino,        dialkylamino or C₃-C₆ cycloalkyl;-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂R, —CO₂alkyl, —C(O)NR₆R₇, —C(O)R₆,    —N(R₃₀)C(O)NR₁₆R₁₇, —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇,    arylalkoxy, heteroaryl, arylalkyl, hydroxyalkyl, dihydroxyalkyl,    haloalkyl, —NR₆R₇, —C(O)NR₆R₇, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the heteroaryl or aryl portions of the above are unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, hydroxy, alkoxy, alkyl,        —CO₂—(C₁-C₆)alkyl, —CONR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆)alkyl-, nitro,        haloalkyl, or haloalkoxy; and-   R₅ is H, arylalkyl, alkyl optionally substituted with 1, 2, or 3    groups that are independently arylalkoxycarbonyl, —NR₈R₉, halogen,    C(O)NR₈R₉, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally    substituted with one trimethylsilyl group, alkoxycarbonyl, amino,    hydroxyalkyl, dihydroxyalkyl, alkenyl optionally substituted with    alkoxycarbonyl, alkynyl, —SO₂-alkyl, aryl, alkoxy optionally    substituted with one trimethylsilyl group, heterocycloalkylalkyl,    heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        arylalkoxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, —SO₂alkyl,        alkoxycarbonyl, arylalkoxycarbonyl, CO₂R, CN, OH, amidinooxime,        NR₈R₉, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, hydroxyalkyl,        dihydroxyalkyl, carboxaldehyde, —NR₆R₇, haloalkyl, —(C₁-C₄        alkyl)-C(O)NR₆R₇, —(C₁-C₄ alkyl)-CO₂R, —(C₁-C₄ alkyl)-C₁-C₆        alkoxycarbonyl, —(C₁-C₄ alkyl)-CN, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈,        —O—CH₂—O—, —O—CH₂CH₂—O—, phenyl or haloalkoxy;        -   R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;        -   R₉ is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl,            monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl.

Embodiment 3

Compounds according to embodiment 2 wherein

-   R₁ is H, halogen, alkyl optionally substituted with C₁-C₄    alkoxycarbonyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl,    phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, CN, alkanoyl, alkoxy, C₂-C₄    alkynyl, C₂-C₆ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, alkoxyalkyl, haloalkyl, or phenyl(C₁-C₆)alkanoyl,    -   wherein the phenyl groups are unsubstituted or substituted with        1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂R;

wherein the alkyl groups are unsubstituted or substituted with 1, 2, or3 groups that are independently halogen, methoxy, or ethoxy;

-   R₂ is OH, phenyl(C₁-C₆)alkoxy, phenyloxy, phenyloxy(C₁-C₆)alkyl,    phenyl(C₁-C₄)thioalkoxy, C₁-C₈ alkoxy, alkoxyalkoxy, —O—SO₂phenyl,    alkynyl, phenyl(C₂-C₄)alkynyl, alkyl, —OC(O)NH(CH₂)_(n)phenyl,    —OC(O)N(alkyl)(CH₂)_(n)phenyl, dialkylamino, pyridyl, pyrimidyl,    pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thienyl, or CO₂R, wherein n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,        haloalkoxy, hydroxyalkyl, dihydroxyalkyl, alkyl, phenyl,        pyridyl, piperidinyl, piperazinyl, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀,        R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇,        —(C₁-C₄ alkyl)-NRC(O)NR₁₆R₁₇, or —OC(O)NR₆R₇, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            (C₁-C₄) hydroxyalkyl, (C₁-C₄) dihydroxyalkyl, (C₁-C₄)alkoxy,            (C₁-C₄)alkoxy (C₁-C₄)alkyl, (C₁-C₄) alkanoyl, phenyl(C₁-C₄)            alkyl, phenyl(C₁-C₄)alkoxy, phenyl(C₁-C₄) alkoxycarbonyl, or            phenyl(C₁-C₄) alkanoyl, wherein each of the above is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, OH, SH, C₃-C₆ cycloalkyl,            (C₁-C₄)alkoxy, (C₁-C₄)alkyl, CF₃, carboxaldehyde, NH₂,            NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, OCF₃; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy            C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxycarbonyl, or            halogen; and-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂R, —CO₂alkyl, —C(O)NR₆R₇, —C(O)R₆,    —N(R₃₀)C(O)NR₁₆R₁₇, —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇,    —C(O)NR₆R₇, phenyl(C₁-C₆)alkoxy, phenyl(C₁-C₆)alkyl, hydroxyalkyl,    dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃, OCF₃;-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl optionally substituted with    1, 2, 3, 4, or 5 groups that are independently phenyl C₁-C₄    alkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉, alkoxycarbonyl, or    alkanoyl, phenyl, alkoxy, C₂-C₆ alkynyl, C₂-C₆ alkenyl optionally    substituted with alkoxycarbonyl, indolyl, quinolinyl, isoquinolinyl,    isoindolyl, dihydroindolyl, pyrazolyl, imidazolyl,    dihydroisoindolyl, indolon-2-yl, indazolyl, benzimidazolyl, pyridyl,    imidazolidine dione, pyrazolyl(C₁-C₆ alkyl), imidazolyl(C₁-C₆    alkyl), piperidinyl(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, tetrahydroisoquinolinyl(C₁-C₆)alkyl,    1H-indazolyl(C₁-C₆)alkyl, dihydroindolon-2-yl(C₁-C₆ alkyl),    indolinyl(C₁-C₆ alkyl), dihydrobenzimidazolyl(C₁-C₆ alkyl), or    dihydrobenzoimidazolonyl(C₁-C₆ alkyl), pyridyl(C₁-C₆) alkyl,    pyridazinyl(C₁-C₆)alkyl, pyrimidinyl(C₁-C₆) alkyl,    pyrazinyl(C₁-C₆)alkyl, tetrahydrofuryl(C₁-C₆)alkyl,    naphthyl(C₁-C₆)alkyl, morpholinyl(C₁-C₆)alkyl,    tetrahydrofuryl(C₁-C₆)alkyl, thienyl(C₁-C₆)alkyl,    piperazinyl(C₁-C₆)alkyl, indolyl(C₁-C₆)alkyl,    quinolinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl,    isoindolyl(C₁-C₆)alkyl, dihydroindolyl(C₁-C₆)alkyl,    pyrazolyl(C₁-C₄)alkyl, imidazolyl(C₁-C₄)alkyl,    dihydroisoindolyl(C₁-C₄)alkyl, indoon-2-yl(C₁-C₆)alkyl,    indolon-2-yl(C₁-C₆)alkyl, or morpholinyl C₁-C₆ alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently C₁-C₆ alkyl, halogen,        C₁-C₆ alkoxy, phenyl C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, C₁-C₆        alkoxycarbonyl, CO₂R, CN, —SO₂(C₁-C₆)alkyl, amidinooxime, NR₈R₉,        —NR₆R₇, NR₆R₇C₁-C₆ alkyl, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇,        amidino, C₁-C₄ haloalkyl, hydroxy C₁-C₆ alkyl, C₁-C₆        dihydroxyalkyl, or C₁-C₄ haloalkoxy; wherein        -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆            alkyl and phenyl C₁-C₆ alkanoyl; and        -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di            C₁-C₆ alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl,            phenyl C₁-C₆ alkyl, indazolyl, and phenyl C₁-C₆ alkanoyl.

Embodiment 4

Compounds according to embodiment 3, wherein

-   R₁ is H, halogen, C₁-C₄ alkyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkynyl, or carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, phenyl    (C₁-C₄)thioalkoxy, or pyridyl; wherein each of the above is    optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇,    —(C₁-C₄)alkyl-C(O)NR₆R₇, (C₁-C₄)haloalkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-NRC(O)NR₁₆R₁₇, (C₁-C₄)haloalkoxy, hydroxyalkyl, C₁-C₆    dihydroxyalkyl, (C₁-C₆)alkyl, pyridyl, or R₆R₇N—(C₁-C₆ alkyl)-.

Embodiment 4a

Compounds according to embodiment 4, wherein R₁ is H.

Embodiment 4b

Compounds according to embodiment 4, wherein R₁ is halogen.

Embodiment 4c

Compounds according to embodiment 4, wherein R₁ is C₁-C₄ alkyloptionally substituted with C₁-C₄ alkoxycarbonyl.

Embodiment 5

Compounds according to embodiment 4, wherein

-   R₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl,    tetrahydroquinolyl, tetrahydroisoquinolyl, pyrazolyl, imidazolyl,    furanyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl,    dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each of which is    unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄    hydroxyalkyl, dihydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl),    benzyloxy, NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, —NR₈R₉, NR₆R₇—(C₁-C₄    alkyl), —C(O)NR₆R₇, or amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl        C₁-C₄ alkoxy, or phenyl C₁-C₄ alkanoyl, wherein each is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, OH, SH, C₃-C₆ cycloalkyl, aryl, C₁-C₄        alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄        dihydroxyalkyl, or halogen.

Embodiment 6

Compounds according to embodiment 5, wherein

-   R₅ is indolyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl, indazolyl,    dihydroindolyl, dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each    of which is unsubstituted or substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃,    C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅    alkyl), benzyloxy, —C(O)NR₆R₇, —NR₈R₉, —(C₁-C₄)alkyl-C(O)NR₆R₇,    —NR₆R₇, NR₆R₇—(C₁-C₄ alkyl)-, and amidinooxime.

Embodiment 7

Compounds according to embodiment 6, wherein

-   R₅ is indolyl, pyridyl, pyrimidinyl, dihydroindolyl,    dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is    unsubstituted or substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄    hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl),    benzyloxy, —C(O)NR₆R₇, NR₈R₉, —(C₁-C₄)alkyl-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇—(C₁-C₄ alkyl)-, or amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄        alkanoyl, C₁-C₄ alkoxy C₁-C₄ alkyl, each of which is optionally        substituted with 1, 2, or 3 groups that are independently        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃.

Embodiment 8

Compounds according to embodiment 7, wherein

-   R₅ is indolyl, pyridyl, pyrimidinyl, dihydroindolyl,    dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, —C(O)NR₆R₇,    —(C₁-C₄)alkyl-C(O)NR₆R₇, NR₈R₉, —NR₆R₇, or NR₆R₇—(C₁-C₄ alkyl)-;    wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkanoyl, or        C₁-C₄ alkoxy, each of which is optionally substituted with 1, 2,        or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

Embodiment 9

Compounds according to embodiment 4, wherein

-   R₅ is phenyl, phenyl(C₁-C₆)alkyl, or (C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, —CO₂(C₁-C₅        alkyl), CO₂R, CN, amidinooxime, —NR₈R₉, —NR₆R₇, R₆R₇N—(C₁-C₆        alkyl)-, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, amidino, CF₃, or        OCF₃;    -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl        and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

Embodiment 10

Compounds according to embodiment 4, wherein

-   R₅ is phenyl, phenyl(C₁-C₆)alkyl, which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —CO₂(C₁-C₅ alkyl),    CO₂R, CN, amidinooxime, —NR₈R₉, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,    R₆R₇NC(O)—(C₁-C₄ alkyl)-, R₆R₇NC(O)—(C₅-C₆ alkyl)-, —C(O)NR₆R₇,    amidino, CF₃, or OCF₃; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl        C₁-C₄ alkoxy, or phenyl C₁-C₄ alkanoyl, wherein each is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,        C₁-C₄ alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl,        or halogen;    -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl        and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

Embodiment 11

Compounds according to embodiment 10, wherein

-   R₅ is phenyl, benzyl or phenethyl, wherein each is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    C₁-C₆ alkyl, —NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₈R₉,    halogen, C₁-C₆ alkoxy, CO₂R, —(C₁-C₄ alkyl)-CO₂R, C₁-C₆ thioalkoxy,    amidinooxime, C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-C₁-C₆    alkoxycarbonyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, —(C₁-C₄    alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, OH, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈,    amidinooxime, —SO₂(C₁-C₆ alkyl), —O—CH₂—O—, —O—CH₂CH₂—O—, phenyl    C₁-C₄ alkoxy, or phenyl; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkanoyl, or        C₁-C₄ alkoxy, each of which is optionally substituted with 1, 2,        or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

Embodiment 12

Compounds according to embodiment 11, wherein

-   R₅ is phenyl, benzyl or phenethyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently CN,    halogen, C₁-C₄ alkoxy, CF₃, OCF₃, C₁-C₄ alkyl, —NR₈R₉, —NR₆R₇,    R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkanoyl, or        C₁-C₄ alkoxy, each of which is optionally substituted with 1, 2,        or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

Embodiment 13

Compounds according to embodiment 4, wherein

the R₅ group is of the formula:

wherein

-   Z₁ and Z₂ are independently H, halogen, C₁-C₄ alkyl, or CO₂R; and-   Z is —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —NR₈R₉, C₁-C₆    hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkyl, CO₂R, or halogen;    wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆        dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or —SO₂(C₁-C₆ alkyl)        each of which is optionally substituted with 1, 2, or 3 groups        that are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄        alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl,        thiomorpholinyl, ring optionally substituted with 1 or 2 groups        that are independently alkyl, hydroxy, hydroxy C₁-C₄ alkyl,        C₁-C₄ dihydroxyalkyl, or halogen; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

Embodiment 14

Compounds according to embodiment 4, wherein

-   R₅ is pyrazolyl(C₁-C₆ alkyl), imidazolyl(C₁-C₆ alkyl), thienyl(C₁-C₆    alkyl), furanyl(C₁-C₆ alkyl), piperidinyl(C₁-C₆)alkyl,    pyrrolidinyl(C₁-C₆)alkyl, imidazolidinyl(C₁-C₆)alkyl,    piperazinyl(C₁-C₆)alkyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, tetrahydroisoquinolinyl(C₁-C₆)alkyl,    indolyl(C₁-C₆)alkyl, 1H-indazolyl(C₁-C₆)alkyl, dihydroindolyl(C₁-C₆    alkyl), dihydroindolon-2-yl(C₁-C₆ alkyl), indolinyl(C₁-C₆ alkyl),    dihydroisoindolyl(C₁-C₆ alkyl), dihydrobenzimdazolyl(C₁-C₆ alkyl),    or dihydrobenzoimidazolonyl(C₁-C₆ alkyl), wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently (C₁-C₆)alkyl, halogen,        (C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, C₁-C₆ dihydroxyalkyl,        phenyl(C₁-C₆)alkoxy, (C₁-C₆)thioalkoxy, (C₁-C₆)alkoxycarbonyl,        phenyl(C₁-C₆)alkoxycarbonyl, OH, CO₂R, CN, amidinooxime, —NR₈R₉,        —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄        alkyl)-C(O)NR₆R₇, amidino, piperazinyl, morpholinyl,        —SO₂(C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₆)alkyl,        —SO₂N(C₁-C₆)alkyl(C₁-C₆)alkyl, (C₁-C₄)haloalkyl, —(C₁-C₄        alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O,        —O—CH₂CH₂—O—, or (C₁-C₄)haloalkoxy; wherein        -   R₆ and R₇ are independently at each occurrence H,            (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,            (C₁-C₆)alkoxycarbonyl, (C₁-C₆)hydroxyalkyl, C₁-C₆            dihydroxyalkyl, —(C₃-C₄)alkyl-CO₂—(C₁-C₆)alkyl,            (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or            phenyl(C₁-C₆)alkanoyl, wherein each of the above is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, (C₁-C₄)alkoxy, OH, SH, C₃-C₆            cycloalkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆            alkyl), (C₁-C₄)alkyl, CF₃ or OCF₃; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy            C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen; and        -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆            alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆            alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or            dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment 15

Compounds according to embodiment 14, wherein

-   R₅ is pyrazolyl(C₁-C₆ alkyl), imidazolyl(C₁-C₆ alkyl),    benzimidazolyl(C₁-C₆ alkyl), thienyl(C₁-C₆ alkyl),    pyrimidyl(C₁-C₆)alkyl, indolyl(C₁-C₆ alkyl), dihydroindolyl(C₁-C₆    alkyl), dihydroisoindolyl(C₁-C₆ alkyl), dihydroindolon-2-yl(C₁-C₆    alkyl), pyridinyl(C₁-C₆ alkyl), piperazinyl(C₁-C₆ alkyl), or    pyrazinyl(C₁-C₆ alkyl) each of which is optionally substituted with    1, 2, or 3 groups that are independently C₁-C₄ alkyl, C₁-C₄    hydroxyalkyl, C₁-C₄ dihydroxyalkyl, halogen, —C(O)NR₆R₇, (C₁-C₄    alkyl)-C(O)NR₆R₇, C₁-C₆ alkoxycarbonyl, NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,    haloalkyl, C₁-C₆ alkanoyl,    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen.

Embodiment 16

Compounds according to embodiment 15, wherein

R₅ is of the formula:

wherein

-   Z₅ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl,    halogen, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₆ alkoxycarbonyl,    R₆R₇N—(C₁-C₆ alkyl)-, —NR₆R₇, CF₃, or C₁-C₆ alkanoyl, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen.

Embodiment 17

Compounds according to embodiment 15, wherein

R₅ is of the formula:

wherein

-   Z₅ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl,    halogen, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₆ alkoxycarbonyl,    R₆R₇N—(C₁-C₆ alkyl)-, —NR₆R₇, CF₃, or C₁-C₆ alkanoyl, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen.

Embodiment 18

Compounds according to either embodiment 16 or 17, wherein

-   Z₅ is C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl,    halogen, C₁-C₆ alkoxycarbonyl, CF₃, or C₁-C₆ alkanoyl.

Embodiment 19

Compounds according to either embodiment 16 or 17, wherein

-   Z₅ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    R₆R₇N—(C₁-C₆ alkyl)-, or —NR₆R₇, CF₃, or C₁-C₄ alkanoyl, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen.

Embodiment 20

Compounds according to embodiment 19, wherein

-   Z₅ is —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, or    —NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, cyclopropyl, OH,        SH, or C₁-C₄ alkoxy.

Embodiment 21

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        haloalkyl, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 22

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄        alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 23

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        haloalkyl, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 24

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄        alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 25

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        haloalkyl, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 26

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄        alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 27

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        haloalkyl, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 28

Compounds according to embodiment 15, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen,        CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄        alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein        R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 29

Compounds according to embodiment 4, wherein

-   R₅ is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl,    dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆    alkoxycarbonyl, CF₃, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈; wherein    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

Embodiment 30

Compounds according to embodiment 29, wherein

-   R₅ is of the formula:

-   Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl;-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl;    and wherein-   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆ alkyl,    amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆    alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆    alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₃-C₆ alkyl),    —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or C₁-C₆ alkanoyl, each of which is    optionally substituted with 1, 2, or 3 groups that are independently    halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH,    CF₃, or OCF₃.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 31

Compounds according to embodiment 30, wherein

R₅ is of the formula:

wherein

-   Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl;-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl, and wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆        dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl),        —SO₂NH₂, SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or        C₁-C₆ alkanoyl, each of which is optionally substituted with 1,        2, or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 32

Compounds according to embodiment 30, wherein

R₅ is of the formula:

wherein

-   Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl;-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄    haloalkyl, and wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆        dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl),        —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl),        or C₁-C₆ alkanoyl, each of which is optionally substituted with        1, 2, or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 33

Compounds according to embodiment 29, wherein

-   R₅ is either

-   -   wherein

-   Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and

-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, —(C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O) R₁₈;

-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, —(C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈;    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen;    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 34

Compounds according to embodiment 33, wherein

R₅ is of the formula:

-   Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, —(C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈;-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, —(C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈;    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or        halogen;    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 35

Compounds according to embodiment 33, wherein

R₅ is of the formula:

wherein

-   Z₁ is H, halogen, C₁-C₄ alkyl C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,    C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and-   Z₂ is C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, (C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈;-   Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl, —(C₁-C₄    alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈;    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring,        each of which is optionally substituted with 1 or 2 groups that        are independently alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄        dihydroxyalkyl, or halogen;    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or        dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that at least one of Z₁, Z₂, and Z₃is not hydrogen.

Embodiment 36

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

-   L and M are independently selected from —O—, —CH₂—, —S—, —NR—,    —N(R)—N(R)—, C(═O)—, —SO₂—;    R₅ is

wherein

-   X₁, X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) at are independently    selected from —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, H, OH, halogen,    haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C₃-C₇    cycloalkyl, R₆R₇N—(C₁-C₆ alkyl)-, —CO₂—(C₁-C₆)alkyl, —N(R)C(O)NR₆R₇,    —N(R)C(O)—(C₁-C₆)alkoxy, CO₂R—(C₁-C₆ alkyl)-, or —SO₂NR₆R₇; wherein    the heteroaryl and heterocycloalkyl groups are optionally    substituted with —NR₆R₇, —C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆    alkyl, C₁-C₆ alkoxy, or halogen; or-   R₅ is heteroaryl or heteroarylalkyl, wherein the heteroaryl and    heteroaryl groups are optionally substituted with 1, 2, 3, or 4    groups that are independently —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    —NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, H, OH, halogen,    haloalkyl, alkyl, haloalkoxy, R₆R₇N—(C₁-C₆ alkyl)-,    —CO₂—(C₁-C₆)alkyl, —N(R)C(O)NR₆R₇, or —N(R)C(O)—(C₁-C₆)alkoxy;    wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₆        thiohydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl,        C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆        alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen;

R at each occurrence is independently H or C₁-C₆ alkyl; and

-   Y, Y₁, Y₂, Y₃, and Y₄ are independently selected from H, halogen,    alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl,    alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, and carboxyl.

Embodiment 37

Compounds according to embodiment 36 of the formula

or a pharmaceutically acceptable salt thereof.

Embodiment 38

Compounds according to embodiment 37, wherein

-   -   R₅ is

Embodiment 39

Compounds according to embodiment 31, wherein

Y₂, Y₄, and Y are independently halogen; and

Y₁ and Y₃ are both hydrogen.

Embodiment 40

Compounds according to embodiment 39, wherein

-   -   R₅ is

-   X₁ and X₂ are independently H, methyl, NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, C₁-C₆    hydroxyalkyl, C₁-C₆ dihydroxyalkyl, or —(C₁-C₄ alkyl)-morpholinyl;    and-   X_(a) and X_(e) are independently halogen, NH₂, NH(C₁-C₆ alkyl),    N(C₁-C₆ alkyl)(C₁-C₆ alkyl), methyl, or hydrogen.

In this embodiment, it is preferred that one of X_(a) and X_(e) is nothydrogen.

Embodiment 41

Compounds according to embodiment 40, wherein

one of X_(b) and X_(c) is hydrogen and the other is —NR₆R₇, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, —SO₂NR₆R₇, or halogen; where

-   -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, —(C₁-C₄)alkyl-CO₂        alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆        alkoxy, or phenyl C₁-C₆ alkanoyl, wherein each of the above is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,        piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl        C₁-C₆ alkyl, OH, SH, NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄        alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen.

Embodiment 42

Compounds according to embodiment 41, wherein

-   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₆    alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, OH, C₁-C₆    hydroxyalkyl, C₁-C₆ dihydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl    C₁-C₆ alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl    C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or    substituted with 1, 2, or 3 groups that are independently, halogen,    C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl    C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, NH₂, NH(alkyl),    N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃.

Embodiment 43

Compounds according to embodiment 42, wherein

-   X_(a) is hydrogen, methyl, fluorine, or chlorine;-   X_(c) and X_(d) are both hydrogen;-   X_(b) is —NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,    —C(O)NR₆R₇; wherein-   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₆    hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆    alkyl, or C₁-C₆ alkanoyl, wherein each of the above is optionally    substituted with 1, 2, or 3 groups that are independently OH, SH,    halogen, or C₃-C₆ cycloalkyl.

Embodiment 44

Compounds according to embodiment 39, wherein

-   -   R₅ is

X_(a) is H, fluoro, chloro, or methyl;X_(e) is hydrogen, halogen, or methyl; andX_(b) is H;X_(d) is H or halogen;

Embodiment 45

Compounds according to embodiment 44, wherein

X_(c) is —SO₂NR₆R₇, or halogen; wherein

-   -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,        —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,        benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, wherein        each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently, halogen, C₃-C₆ cycloalkyl,        C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,        piperazinyl C₁-C₆ alkyl, OH, SH, NH₂, NH(alkyl),        N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃;        or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen;        or

-   X_(c) is fluoro, chloro, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆    alkyl)(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆    alkyl)(C₁-C₆ alkyl), or piperazinyl, wherein the piperazinyl group    is optionally substituted with 1 or 2 groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄    dihydroxyalkyl, or halogen.

Embodiment 46

Compounds according to embodiment 44, wherein

-   X_(c) is —C(O)NR₆R₇, —(C₁-C₆ alkyl)-C(O)NR₆R₇, —NR₆R₇, or    R₆R₇N—(C₁-C₆ alkyl)-; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        dihydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl,        C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆        alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH,        —NH₂, —NH(alkyl), —N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄        alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen.

Embodiment 47

Compounds according to embodiment 46, wherein

-   R₆ is hydrogen; and-   R₇ is C₁-C₆ alkyl or C₁-C₆ alkanoyl, each of which is optionally    substituted with 1, 2, or 3 groups that are independently NH₂,    NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, SH, cyclopropyl,    or C₁-C₄ alkoxy;

Embodiment 48

Compounds according to embodiment 47, wherein

X_(c) is —C(O)NR₆R₇.

Embodiment 49

Compounds according to embodiment 47, wherein

X_(c) is NR₆R₇, or R₆R₇N—(C₁-C₆ alkyl)-.

Embodiment 50

Compounds according to embodiment 38, wherein

X_(a) is hydrogen;

-   two of X_(b), X_(c), and X_(d) are hydrogen and the other is    —C(O)NR₆R₇, —(C₁-C₆ alkyl)-C(O)NR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-    or —CO₂—(C₁-C₆)alkyl; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,        —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,        benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, wherein        each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently, halogen, C₃-C₆ cycloalkyl,        C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,        piperazinyl C₁-C₆ alkyl, OH, NH₂, NH(alkyl), N(alkyl)(alkyl),        —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄        alkyl, C₁-C₄ dihydroxyalkyl, or halogen; and        X_(e) is hydrogen, methyl, C₁-C₂ alkoxy, or halogen.

Embodiment 51

Compounds according to embodiment 50, wherein

-   X_(b) is —C(O)NR₆R₇, —(C₁-C₆ alkyl)-C(O)NR₆R₇, —NR₆R₇, or    R₆R₇N—(C₁-C₆ alkyl)- wherein-   R₆ is hydrogen or C₁-C₄ alkyl;-   R₇ is OH, C₁-C₆ alkyl or C₁-C₆ alkanoyl, wherein the alkyl and    alkanoyl groups substituted with 1, 2, or 3 groups that are    independently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl),    C₃-C₆ cycloalkyl, OH, or C₁-C₄ alkoxy.

Embodiment 52

Compounds according to embodiment 38, wherein

-   X_(a) is halogen or methyl;-   X_(b) is H, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, or    —CO₂—(C₁-C₆)alkyl;-   X_(c) is —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, halogen,    —CO₂—(C₁-C₆)alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆    alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆    alkyl), or piperazinyl, wherein the piperazinyl group is optionally    substituted with 1 or 2 groups that are independently C₁-C₄ alkyl,    C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or    halogen;-   X_(d) is hydrogen;-   X_(e) is H, methyl, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆    alkyl).

Embodiment 53

Compounds according to embodiment 38, wherein

-   X₁, X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) are independently    selected from H, OH, halogen, CF₃, alkyl, OCF₃, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,    piperidinyl, piperazinyl, or C₃-C₇ cycloalkyl, wherein each of the    above is optionally substituted with NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy,    or halogen.

Embodiment 54

Compounds according to embodiment 37, wherein

-   R₅ is a heteroaryl or heteroarylalkyl group, where each heteroaryl    is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, dihydroindolyl,    dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl,    tetrahydroisoquinolinyl, dihydroisoquinolinyl, or indolyl, each of    which is optionally substituted with 1, 2, 3, or 4 groups that are    independently —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,    hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, hydrogen, hydroxy,    halogen, haloalkyl, alkyl, haloalkoxy, R₆R₇N—(C₁-C₆ alkyl)-,    —CO₂—(C₁-C₆)alkyl, —N(R)C(O)NR₆R₇, or —N(R)C(O)—(C₁-C₆)alkoxy;    wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆        thiohydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl,        C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆        alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF.

Embodiment 55

Compounds according to embodiment 54, wherein

Y₂, Y₄, and Y are independently halogen; and

Y₁ and Y₃ are both hydrogen.

Embodiment 56

Compounds according to embodiment 55, wherein

-   X₁ and X₂ are independently H, methyl, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₆ hydroxyalkyl, C₁-C₆    dihydroxyalkyl, or —(C₁-C₄ alkyl)-morpholinyl.

Embodiment 57

Compounds according to embodiment 56, wherein

-   R₅ is pyridyl C₁-C₆ alkyl, pyrimidinyl C₁-C₆ alkyl, or pyrazinyl    C₁-C₆ alkyl, each of which is optionally substituted with 1, 2, or 3    groups that are independently hydroxy(C₁-C₄)alkyl, C₁-C₄    dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,    —(C₁-C₄ alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇.

Embodiment 58

Compounds according to embodiment 57, wherein

R₅ is of the formula:

wherein

-   Z₅ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen, CF₃,    (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄    alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 59

Compounds according to embodiment 57, wherein

R₅ is of the formula:

wherein

-   Z₅ is hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen, CF₃,    (C₁-C₄)alkyl, OCF₃, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄    alkyl)-C(O)NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 60

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is (C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 61

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 62

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 63

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 64

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 65

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 66

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, —NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment 67

Compounds according to embodiment 57, wherein

-   -   R₅ is of the formula:

wherein

-   -   Z₁₀ is H or methyl; and    -   Z₂₀ is —(C₁-C₄ alkyl)-C(O)NR₆R₇, hydroxy(C₁-C₄)alkyl, C₁-C₄        dihydroxyalkyl, OH, halogen, CF₃, (C₁-C₄)alkyl, OCF₃, NR₆R₇,        R₆R₇N—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy.

Embodiment A7

Compounds according to embodiment 1 wherein

-   R₁ is H, halogen, alkyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₆ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, carboxaldehyde,    C₁-C₄ hydroxyalkyl, phenyl(C₁-C₆)alkoxy, benzyl, phenethyl,    phenpropyl, CN, or phenyl(C₁-C₆)alkanoyl,    -   wherein the phenyl groups are unsubstituted or substituted with        1, 2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is OH, benzyloxy, phenyloxy, phenyloxy(C₁-C₆)alkyl, phenyl    (C₁-C₄)thioalkoxy, —OC(O)NH(CH₂)_(n)phenyl,    —OC(O)N(alkyl)(CH₂)_(n)phenyl, di(C₁-C₆)alkylamino, C₂-C₆ alkynyl,    pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl,    tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl,    pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,    hexahydropyrimidinyl, thiazolyl, thienyl, or CO₂H, wherein n is 0,    1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen, NR₆R₇,        (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, (C₁-C₆) alkyl, pyridyl,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, or NR₆R₇—(C₁-C₆ alkyl)-,-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenyl(C₁-C₆)alkoxy,    phenyl(C₁-C₆)alkyl, hydroxyalkyl, wherein the phenyl groups are    unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are    independently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, or OCF₃;    and-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl,    piperidinyl(C₁-C₆)alkyl, thienyl(C₁-C₆)alkyl, indolyl, quinolinyl,    isoquinolinyl, isoindolyl, indol-2-onyl, indazolyl,    indolyl(C₁-C₆)alkyl, quinolinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, isoindolyl(C₁-C₆)alkyl, indol-2    onyl(C₁-C₆)alkyl, naphthyl(C₁-C₆)alkyl, pyridyl(C₁-C₆)alkyl,    pyrimidyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl, or wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, thioalkoxy, —CO₂(C₁-C₅ alkyl), CO₂H, CN,        amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino,        CF₃, or OCF₃; R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl,        phenyl C₁-C₆ alkyl and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

In this embodiment, it is preferred that when R₂ is benzyloxy, R₄ is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A8

Compounds according to embodiment A7 wherein

-   R₁ is H, halogen, C₁-C₄ alkyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkynyl, or carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, phenyl    (C₁-C₄)thioalkoxy, or pyridyl; wherein each of the above is    optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇,    (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or    NR₆R₇—(C₁-C₆ alkyl)-.

Embodiment A9

Compounds according to embodiment A7 wherein

-   R₄ is H, (C₁-C₆)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenyl(C₃-C₆)alkoxy, or    hydroxy(C₁-C₆)alkyl, wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, hydroxy, C₁-C₄ alkoxy,        C₁-C₄ alkyl, nitro, CF₃, OCF₃; and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, indolyl    (C₁-C₆)alkyl, naphthyl(C₁-C₆)alkyl, thienyl(C₁-C₆)alkyl,    pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl, or    pyrazinyl(C₁-C₆)alkyl, and wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, thioalkoxy, —CO₂(C₁-C₅ alkyl), CF₃, OCF₃, CO₂H, CN,        amidinooxime.

In this embodiment, it is preferred that when R₂ is benzyloxy, R₄ is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A10

Compounds according to embodiment A7, wherein

-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenyl(C₁-C₆)alkoxy, benzyl,    phenethyl, phenpropyl, or hydroxy(C₁-C₆)alkyl, wherein    -   the phenyl groups are unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, hydroxy, C₁-C₄ alkoxy,        C₁-C₄ alkyl, nitro, CF₃, OCF₃; and-   R₅ is indolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl,    indolyl(C₁-C₆)alkyl, quinolinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, isoindolyl(C₁-C₆)alkyl,    indol-2-onyl(C₁-C₆)alkyl, each of which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently C₁-C₄    alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄ hydroxyalkyl, C₁-C₄    alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, —NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-,    —C(O)NR₆R₇, or amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl,        hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl,        phenylalkoxy, or phenylalkanoyl, wherein each is unsubstituted        or substituted with 1, 2, or 3 groups that are independently,        halogen, hydroxy, C₁-C₄ alkoxy, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄        alkyl, CF₃, or OCF₃; or-   R₆, R₇, and the nitrogen to which they are attached form a    morpholinyl, thiomorpholinyl, or piperazinyl ring which is    optionally substituted with 1 or 2 groups that are independently    C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A11

Compounds according to embodiment A7 wherein

-   R₁ is chloro, bromo, iodo, or H; and-   R₅ is benzyl, phenethyl, phenpropyl, phenyl, quinolinyl, indolyl,    isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(C₁-C₆)alkyl,    quinolinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl,    isoindolyl(C₁-C₆)alkyl, indol-2-onyl(C₁-C₆)alkyl, piperidinyl C₁-C₄    alkyl, thienyl C₁-C₄ alkyl, —CH₂-pyridyl, or pyridyl, each of which    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, C₁-C₄ hydroxyalkyl,    C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, NR₈R₉, NR₆R₇C₁-C₄ alkyl,    —C(O)NR₆R₇, and amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, alkyl,        hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl,        phenylalkoxy, or phenylalkanoyl, wherein each is unsubstituted        or substituted with 1, 2, or 3 groups that are independently,        halogen, hydroxy, C₁-C₄ alkoxy, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄        alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A12

Compounds according to embodiment A11, wherein

-   R₅ is benzyl, phenethyl, phenpropyl, or phenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄    hydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, NR₈R₉,    NR₆R₇C₁-C₄ alkyl, —C(O)NR₆R₇, and amidinooxime.

Embodiment A13

Compounds according to embodiment A11, wherein

-   R₅ is quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-onyl,    indolyl(C₁-C₆)alkyl, quinolinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, isoindolyl(C₁-C₆)alkyl,    indol-2-onyl(C₁-C₆)alkyl, piperidinyl C₁-C₄ alkyl, thienyl C₁-C₄    alkyl, —CH₂-pyridyl, or pyridyl, each of which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently C₁-C₄    alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄ hydroxyalkyl, C₁-C₄    alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, NR₈R₉, NR₆R₇C₁-C₄ alkyl,    —C(O)NR₆R₇, and amidinooxime.

Embodiment A14

Compounds according to any one of embodiments A11, A12, or A13 wherein

-   R₂ is benzyloxy, or phenethyloxy;    -   each of the above is unsubstituted or substituted with 1, 2, or        3, groups that are independently —(C₁-C₆)alkyl N(R)—CO₂R₃₀,        fluoro, chloro, bromo, CF₃, or (C₁-C₄)alkyl.

Embodiment A15

Compounds according to any one of embodiments A11, A12 or A13 wherein

-   R₂ is phenyloxy(C₁-C₆)alkyl, wherein the phenyl group is    unsubstituted or substituted with 1, 2, or 3, groups that are    independently —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, fluoro, chloro, bromo, CF₃,    or (C₁-C₄)alkyl.

Embodiment A16

Compounds according to embodiment A1, wherein

-   R₁ is H, halogen, C₁-C₄ alkyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkynyl, or carboxaldehyde.

Embodiment A17

Compounds according to embodiment A16, wherein

-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-.

Embodiment A18

Compounds according to embodiment A17, wherein

-   R₄ is H, or (C₁-C₄)alkyl optionally substituted with one or two    groups that are independently CO₂H, —CO₂alkyl, —C(O)NRR,    —N(R₃₀)C(O)NRR, —N(R₃₀)C(O)—(C₁-C₆)alkoxy, OH, or —NR₆R₇.

Embodiment A19

Compounds according to embodiment A18, wherein

-   R₅ is phenyl, naphthyl, indolyl, pyridyl, quinolinyl, isoquinolinyl,    isoindolyl, indol-2-onyl, indolyl(C₁-C₆) alkyl,    quinolinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl,    isoindolyl(C₁-C₆)alkyl, indol-2-onyl(C₁-C₆)alkyl, pyridazinyl,    pyrimidinyl, or pyrazinyl, pyridazinyl(C₁-C₆) alkyl,    pyrimidinyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl, each of which is    unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are    independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄    hydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, —NR₈R₉,    —C(O)NR₆R₇, NR₆R₇C₁-C₄ alkyl, and amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,        C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkoxy, or        phenyl C₁-C₄ alkanoyl, wherein each is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, SH, C₃-C₆        cycloalkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A20

Compounds according to embodiment A19, wherein

-   R₁ is H, halogen, methyl, ethyl, C₂-C₄ alkenyl C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, NR₆R₇C₁-C₄ alkyl,    (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, or pyridyl; and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, OH, or —NR₆R₇.

Embodiment A21

Compounds according to embodiment A20, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, —NR₁₀R₁₁, C₁-C₄ alkoxy,    —C(O)NR₁₀R₁₁, —CO₂H, NR₁₀R₁₁C₁-C₄ alkyl, C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkoxy, CHO, —SO₂NH₂, C₁-C₄ haloalkyl, C₁-C₆    hydroxyalkyl, —C₁-C₄ alkyl-NR₁₂C(O)NR₁₃R₁₄, —C₁-C₄    alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-NR₁₃R₁₄, —C₁-C₄ alkyl-NR₁₂C(O)OR₁₅, or    —C₁-C₄ alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-R₁₅, wherein    -   R₁₀ and R₁₁ at each occurrence are independently H, C₁-C₆ alkyl,        amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆        alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl,        OH, —SO₂(C₁-C₆ alkyl), or C₁-C₆ alkanoyl, or    -   R₁₀, R₁₁, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl or halogen,    -   R₁₂ is H or C₁-C₆ alkyl;    -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; or    -   R₁₃ and R₁₄ and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₅ is C₁-C₆ alkoxy; —OC(O)C₁-C₆ alkyl, OH.

Embodiment A22

Compounds according to embodiment A21, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, —NR₁₀R₁₁, NR₁₀R₁₁C₁-C₆    alkyl, C₁-C₄ alkoxy, or —C(O)NR₁₀R₁₁, —CO₂H, —C₁-C₄ alkyl-NR₁₀R₁₁,    C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxy, CHO, —SO₂NH₂, C₁-C₄    haloalkyl, C₁-C₆ hydroxyalkyl, —C₁-C₄ alkyl-NR₁₂C(O)NR₁₃R₁₄, —C₁-C₄    alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-NR₁₃R₁₄, —C₁-C₄ alkyl-NR₁₂C(O)OR₁₅, or    —C₁-C₄ alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-R₁₅ wherein    -   R₁₀ and R₁₁ at each occurrence are independently H, C₁-C₆ alkyl,        amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆        alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl,        OH, —SO₂(C₁-C₆ alkyl), or C₁-C₆ alkanoyl,    -   R₁₂ is H or C₁-C₆ alkyl;    -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; or    -   R₁₃ and R₁₄ and the nitrogen to which they are attached form a        morpholinyl ring; and    -   R₁₅ is C₁-C₆ alkoxy; —OC(O)C₁-C₆ alkyl, OH.

Embodiment A23

Compounds according to embodiment A22, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, —NR₁₀R₁₁, NR₁₀R₁₁C₁-C₄    alkyl, C₁-C₄ alkoxy, —C(O)NR₁₀R₁₁, wherein    -   R₁₀ and R₁₁ at each occurrence are independently H, C₁-C₆ alkyl,        amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆        alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl,        OH, —SO₂(C₁-C₆ alkyl), C₁-C₆ alkanoyl.

Embodiment A24

Compounds according to embodiment A23, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, —NR₁₀R₁₁, or C₁-C₄    alkoxy.

Embodiment A25

Compounds according to embodiment A23, wherein

-   R₅ is substituted with at least one —C(O)NR₁₀R₁₁.

Embodiment A26

Compounds according to embodiment A25, wherein

-   R₁₀ and R₁₁ at each occurrence are independently H, C₁-C₆ alkyl,    amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆    alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl.

Embodiment 27

Compounds according to embodiment A26, wherein

R₁₀ is H.

Embodiment A28

Compounds according to embodiment A25, wherein

R₁₀ and R₁₁ at each occurrence are independently H, C₁-C₆ alkyl, OH,—SO₂(C₁-C₆ alkyl), C₁-C₆ alkanoyl.

Embodiment A29

Compounds according to embodiment A20, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl),    N(C₁-C₆ alkyl)(C₁-C₆ alkyl), C₁-C₄ alkoxy, —C(O)NR₁₀R₁₁, wherein    each of the above alkyl groups is optionally substituted with 1 or 2    groups that are independently OH, or methoxy; wherein    -   R₁₀, R₁₁, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl or halogen.

Embodiment A30

Compounds according to embodiment A20, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, —CO₂H,    —C₁-C₄ alkyl-NR₁₀R₁₁, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxy, CHO,    —SO₂NH₂, C₁-C₄ haloalkyl, C₁-C₆ hydroxyalkyl, —C₁-C₄    alkyl-NR₁₂C(O)NR₁₃R₁₄, —C₁-C₄ alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-NR₁₃R₁₄,    —C₁-C₄ alkyl-NR₁₂C(O)OR₁₅, or —C₁-C₄ alkyl-NR₁₂C(O)—(C₁-C₄    alkyl)-R₁₅, —OC(O)C₁-C₆ alkyl, or OH wherein    -   R₁₂ is H or C₁-C₆ alkyl;    -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; or    -   R₁₃ and R₁₄ and the nitrogen to which they are attached form a        morpholinyl ring;    -   R₁₅ is C₁-C₆ alkoxy.

Embodiment A31

Compounds according to embodiment A30, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —CO₂H,    C₁-C₄ alkoxycarbonyl, C₁-C₄ alkoxy, CHO, —SO₂NH₂, C₁-C₄ haloalkyl,    C₁-C₄ hydroxyalkyl.

Embodiment A32

Compounds according to embodiment A30, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —CO₂H,    —C₁-C₄ alkyl-NR₁₀R₁₁, —C₁-C₄ alkyl-NR₁₂C(O)NR₁₃R₁₄, —C₁-C₄    alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-NR₁₃R₁₄, —C₁-C₄ alkyl-NR₁₂C(O)OR₅, or    —C₁-C₄ alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-R₁₅, or OC(O)C₁-C₆ alkyl,    wherein    -   R₁₂ is H or C₁-C₆ alkyl;    -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; or    -   R₁₃ and R₁₄ and the nitrogen to which they are attached form a        morpholinyl ring;    -   R₁₅ is C₁-C₆ alkoxy.

Embodiment A33

Compounds according to embodiment A31, wherein

-   R₅ is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —CO₂H,    —C₁-C₄ alkyl-NR₁₀R₁₁, —C₁-C₄ alkyl-NR₁₂C(O)NR₁₃R₁₄, —C₁-C₄    alkyl-NR₁₂C(O)—(C₁-C₄ alkyl)-NR₁₃R₁₄, wherein    -   R₁₂ is H or C₁-C₆ alkyl;    -   R₁₃ and R₁₄ are independently H or C₁-C₆ alkyl; or    -   R₁₃ and R₁₄ and the nitrogen to which they are attached form a        morpholinyl ring.

Embodiment A34

Compounds according to any one of embodiments A30, A31, A32, or A33,wherein the phenyl group is substituted with two groups that are meta toeach other.

Embodiment A35

Compounds according to any one of embodiments A30, A31, A32, or A33,wherein the phenyl group is substituted with two groups that are para toeach other.

Embodiment A36

Compounds according to embodiment A20, wherein

-   R₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl,    quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, pyridazinyl,    pyrimidinyl, or pyrazinyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4 or 5 groups that are independently C₁-C₄    alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄ hydroxyalkyl, C₁-C₄    alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, NR₈R₉, NR₆R₇C₁-C₄ alkyl,    —C(O)NR₆R₇, or amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,        C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkoxy, or        phenyl C₁-C₄ alkanoyl, wherein each is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A38

Compounds according to embodiment A36, wherein

-   R₅ is indolyl, pyridyl, pyrimidinyl, indazolyl, or pyrazinyl, each    of which is unsubstituted or substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃,    C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy,    —C(O)NR₆R₇, —NR₈R₉, NR₆R₇C₁-C₄ alkyl, and amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,        C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkoxy, or        phenyl C₁-C₄ alkanoyl, wherein each is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃

Embodiment A39

Compounds according to embodiment A38, wherein

-   R₅ is indolyl, pyridyl, or pyrazinyl, each of which is unsubstituted    or substituted with 1, 2, 3, or 4 groups that are independently    C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃, C₁-C₄ hydroxyalkyl, C₁-C₄    alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy, —C(O)NR₆R₇, NR₈R₉, NR₆R₇—C₁-C₄    alkyl-, and amidinooxime; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, each        of which is optionally substituted with 1, 2, or 3 groups that        are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄        alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

Embodiment A40

Compounds according to embodiment A36, wherein

-   R₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each    of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups    that are independently C₁-C₄ alkyl, halogen, CF₃, OCF₃, —CO₂CH₃,    C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, —CO₂(C₁-C₅ alkyl), benzyloxy,    —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl) wherein the alkyl group is optionally    substituted with OH or methoxy, —C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl)    wherein each alkyl group is independently and optionally substituted    with OH or methoxy, —C(O)NR₆R₇, NR₈R₉, NR₆R₇C₁-C₄ alkyl, —C₁-C₄    alkyl-NH₂, —C₁-C₄ alkyl-NH(C₁-C₆ alkyl) wherein each alkyl group is    independently and optionally substituted with OH or methoxy, —C₁-C₄    alkyl-N(C₁-C₆ alkyl)(C₁-C₆ alkyl) wherein each alkyl group is    independently and optionally substituted with OH or methoxy, and    amidinooxime; wherein    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A42

Compounds according to any one of embodiments A37, A38, A39, or A40,wherein

-   R₁ is H, halogen, methyl, or carboxaldehyde;-   R₂ is benzyloxy, phenyloxy, phenyloxy(C₁-C₆)alkyl, or phenyl    (C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, NR₆R₇(C₁-C₆)alkyl, pyridyl,    morpholinyl, thiomorpholinyl, piperazinyl pyridyl(C₁-C₆)alkyl,    morpholinyl(C₁-C₆)alkyl, thiomorpholinyl(C₁-C₆)alkyl, or    piperazinyl(C₁-C₆)alkyl wherein the pyridyl, morpholinyl,    thiomorpholinyl, and piperazinyl rings are optionally substituted    with 1 or 2 groups that are independently C₁-C₄ alkyl, or halogen;    -   wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl        optionally substituted with 1 or two groups that are        independently OH, halogen or methoxy, C₁-C₄ hydroxyalkyl, C₁-C₄        alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₄ alkanoyl, benzyl,        benzyloxy, or phenyl C₁-C₄ alkanoyl, wherein each is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,        C₁-C₄ alkyl, CF₃, or OCF₃, and-   R₄ is H, (C₁-C₃)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, —NR₆R₇, NR₆R₇C₁-C₄ alkyl, or    hydroxy(C₁-C₃)alkyl.

Embodiment A43

Compounds according to embodiment A42, wherein

R₁ is H or halogen.

Embodiment A44

Compounds according to embodiment A18, wherein

-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, piperidinyl(C₁-C₆)alkyl,    thienyl(C₁-C₆)alkyl, indolyl(C₁-C₆)alkyl, naphthyl(C₁-C₆)alkyl,    pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl, quinolinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, isoindolyl(C₁-C₆)alkyl,    indol-2-onyl(C₁-C₆)alkyl, pyridazinyl(C₁-C₆)alkyl,    pyrazinyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        benzyloxy, hydroxyalkyl, thioalkoxy, —CO₂(C₁-C₅ alkyl), CO₂H,        CN, amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇,        amidino, CF₃, or OCF₃;        -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆            alkyl and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

In this embodiment, it is preferred that when R₂ is benzyloxy, P4 is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A45

Compounds according to embodiment A44, wherein

-   R₅ is phenyl(C₁-C₆)alkyl, which is unsubstituted or substituted with    1, 2, 3, 4, or 5 groups that are independently alkyl, halogen,    alkoxy, benzyloxy, thioalkoxy, —CO₂(C₁-C₅ alkyl), CO₂H, CN,    amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, CF₃,    or OCF₃; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,        C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkoxy, or        phenyl C₁-C₄ alkanoyl, wherein each is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen;    -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl        and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

Embodiment A46

Compounds according to embodiment A45, wherein

-   R₅ is phenyl(C₁-C₆)alkyl, which is unsubstituted or substituted with    1, 2, 3, 4, or 5 groups that are independently CN, halogen, C₁-C₄    alkoxy, C₁-C₄ thioalkoxy, C₁-C₄ haloalkyl, C₁-C₄ alkyl, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, —C(O)NR₂₀R₂₁, wherein    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen.

Embodiment A47

Compounds according to embodiment A46, wherein

-   R₅ is phenyl(C₁-C₄)alkyl, which is unsubstituted or substituted with    1, 2, 3, 4, or 5 groups that are independently CN, halogen, C₁-C₄    alkoxy, C₁-C₄ haloalkyl, C₁-C₄ alkyl, C₁-C₄ haloalkoxy,    —C(O)NR₂₀R₂₁, wherein    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen.

Embodiment A48

Compounds according to embodiment A47, wherein

-   R₅ is benzyl or phenethyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently CN,    halogen, C₁-C₄ alkoxy, CF₃, OCF₃, C₁-C₄ alkyl, —C(O)NR₂₀R₂₁, wherein    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen.

Embodiment A49

Compounds according to embodiment A48, wherein

-   R₅ is benzyl or phenethyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    halogen, methoxy, ethoxy, CF₃, OCF₃, methyl, ethyl, or —C(O)NR₂₀R₂₁,    wherein    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl,

Embodiment A50

Compounds according to embodiment A48, wherein

-   R₅ is benzyl or phenethyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    halogen, methoxy, ethoxy, CF₃, OCF₃, methyl, ethyl, or —C(O)NR₂₀R₂₁,    wherein    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen.

Embodiment A51

Compounds according to embodiment A49, wherein

-   R₅ is substituted on the phenyl ring with 1, 2, 3, 4, or 5 groups    and wherein there is a group at the para position of the phenyl.

Embodiment A52

Compounds according to embodiment A43, wherein

-   R₅ is piperidinyl(C₁-C₆)alkyl, thienyl(C₁-C₆)alkyl, indolyl    (C₁-C₆)alkyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    quinolinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl,    isoindolyl(C₁-C₆)alkyl, indol-2-onyl(C₁-C₆)alkyl,    pyridazinyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl, or    pyrazinyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently C₁-C₆ alkyl, halogen,        C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, benzyloxy, C₁-C₆ thioalkoxy,        —CO₂(C₁-C₅ alkyl), CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆        alkyl)-, —C(O)NR₆R₇, amidino, CF₃, or OCF₃;    -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl        and phenyl C₁-C₆ alkanoyl; and    -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆        alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl        C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.

In this embodiment, it is preferred that when R₂ is benzyloxy, R₄ is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A53

Compounds according to embodiment A52, wherein

-   R₅ is piperidinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, indolyl    (C₁-C₄)alkyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, or    pyrazinyl(C₁-C₄)alkyl, each of which is unsubstituted.

Embodiment A54

Compounds according to embodiment A52, wherein

-   R₅ is indolyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, or    pyrazinyl(C₁-C₄)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        or 4 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆        alkoxy, C₁-C₆ hydroxyalkyl, benzyloxy, C₂-C₆ thioalkoxy,        —CO₂(C₁-C₅ alkyl), CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆        alkyl)-, amidino, —C(O)NR₂₀R₂₁, CF₃, or OCF₃; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl,        C₁-C₄ alkanoyl, benzyl, benzyloxy, or phenyl C₁-C₄ alkanoyl,        wherein each is unsubstituted or substituted with 1, 2, or 3        groups that are independently, halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, or piperazinyl ring which is        optionally substituted with 1 or 2 groups that are independently        C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen;        -   R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₄            alkyl and phenyl C₁-C₄ alkanoyl; and        -   R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl, di            C₁-C₆ alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl,            phenyl C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl;    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen

Embodiment A55

Compounds according to embodiment A54, wherein

-   R₅ is indolyl(C₁-C₄)alkyl, or pyrazinyl(C₁-C₄)alkyl, wherein each of    the above is unsubstituted or substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, C₁-C₆    hydroxyalkyl, benzyloxy, C₁-C₆ thioalkoxy, —CO₂(C₁-C₅ alkyl), CO₂H,    CN, —C(O)NR₂₀R₂₁, CF₃, or OCF₃; wherein    -   R₂₀ and R₂₁ are independently H, C₁-C₆ alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, or    -   R₂₀, R₂₁, and the nitrogen to which they are attached form a        piperazinyl, or morpholinyl ring, each of which is optionally        substituted with 1 or 2 groups that are independently alkyl or        halogen.

Embodiment A56

Compounds according to embodiment A52, wherein

-   R₅ is isoquinolinyl, isoindolyl, indol-2-onyl,    quinolinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl, isoindolyl(C₁-C₆)    alkyl, indol-2-onyl(C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently C₁-C₆ alkyl, halogen,        C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, benzyloxy, C₁-C₆ thioalkoxy,        —CO₂(C₁-C₅ alkyl), CO₂H, CN, amidinooxime, NR₈R₉, NR₆R₇—(C₁-C₆        alkyl)-, —C(O)NR₆R₇, amidino, CF₃, or OCF₃.

Embodiment A57

Compounds according to embodiment A1, wherein

-   R₁ is H, halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, or hydroxy(C₁-C₄)alkyl;-   R₅ is C₃-C₇ cycloalkyl or C₃-C₇ cycloalkylalkyl, each of which is    optionally substituted with 1 or 2 groups that are independently    alkyl, alkoxy, halogen, —NR₆R₇, or NR₆R₇—(C₁-C₆ alkyl)-, wherein    each of the alkyl groups is optionally substituted with 1 or 2    groups that are independently OH, methoxy, NH₂, or halogen.

Embodiment A58

Compounds according to embodiment A57, wherein

-   R₅ is C₃-C₇ cycloalkyl or C₃-C₇ cycloalkyl C₁-C₄ alkyl, each of    which is optionally substituted with 1 or 2 groups that are    independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, —NR₆R₇, or    NR₆R₇—(C₁-C₆ alkyl)- wherein each of the alkyl groups is optionally    substituted with 1 or 2 groups that are independently OH, methoxy,    or NH₂;-   R₆ and R₇ are independently at each occurrence H, C₁-C₄ alkyl, C₁-C₄    hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₄    alkanoyl, benzyl, benzyloxy, or phenyl C₁-C₄ alkanoyl, wherein each    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently, halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,    C₁-C₄ alkyl, CF₃, or OCF₃; or-   R₆, R₇, and the nitrogen to which they are attached form a    morpholinyl, thiomorpholinyl, or piperazinyl ring which is    optionally substituted with 1 or 2 groups that are independently    C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A59

Compounds according to embodiment A58, wherein

-   R₁ is H, halogen, methyl, ethyl;-   R₂ is benzyloxy, phenyloxy, phenyloxy(C₁-C₆)alkyl, or phenyl    (C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl —N(R)—CO₂R₃₀, amino, mono or dialkylamino,    —NR₆R₇, (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, (C₁-C₆)alkyl, or    NR₆R₇—(C₁-C₆ alkyl)-; and-   R₄ is H, methyl, (C₁-C₄)alkyl optionally substituted with one or two    groups that are independently CO₂H, CO₂alkyl, C(O)NRR,    —N(R₃₀)C(O)NRR, —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇ or    hydroxy(C₁-C₂)alkyl.

Embodiment A60

Compounds according to embodiment A59, wherein

-   R₂ is substituted with two halogens and is further optionally    substituted with 1 or 2 groups that are independently halogen,    —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, amino, mono or dialkylamino, —NR₆R₇,    (C₁-C₄)haloalkyl, (C₁-C₄) haloalkoxy, (C₁-C₆)alkyl, or NR₆R₇—(C₁-C₆    alkyl).

Embodiment A61

Compounds according to embodiment A1, wherein

-   R₅ is H, alkyl optionally substituted with 1, 2, or 3 groups that    are independently phenylalkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉,    alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with    one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl,    alkenyl optionally substituted with alkoxycarbonyl, alkynyl,    —SO₂-alkyl, or alkoxy optionally substituted with one trimethylsilyl    group, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, —SO₂alkyl, alkoxycarbonyl,        phenylalkoxycarbonyl, CO₂H, CN, OH, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, hydroxyalkyl,        carboxaldehyde, —NR₆R₇, haloalkyl, or haloalkoxy;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, phenylalkyl and            arylalkanoyl; and        -   wherein R₉ is alkyl, alkanoyl, phenylalkyl, heteroaryl,            aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and            arylalkanoyl.

In this embodiment, it is preferred that when R₂ is benzyloxy, R₄ is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A62

Compounds according to embodiment A1, wherein

-   R₅ is H, alkyl optionally substituted with 1, 2, or 3 groups that    are independently phenylalkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉,    alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with    one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl,    alkenyl optionally substituted with alkoxycarbonyl, alkynyl,    —SO₂-alkyl, alkoxy optionally substituted with one trimethylsilyl    group, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        phenylalkoxy, thioalkoxy, —SO₂alkyl, alkoxycarbonyl,        phenylalkoxycarbonyl, CO₂H, CN, OH, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, hydroxyalkyl,        carboxaldehyde, —NR₆R₇, haloalkyl, or haloalkoxy;        -   wherein R₈ is hydrogen, alkyl, alkanoyl, phenylalkyl and            arylalkanoyl; and    -   wherein R₉ is alkyl, alkanoyl, phenylalkyl, heteroaryl,        aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and        arylalkanoyl.

In this embodiment, it is preferred that when R₂ is benzyloxy, R₄ is H,and R₅ is benzyl or methyl, R₁ is not hydrogen; and

no more than two of R₁, R₂, R₄, and R₅ are simultaneously hydrogen.

Embodiment A63

Compounds according to embodiment A62, wherein

-   R₁ is H, halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (Cl-0-4)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, or hydroxy(C₁-C₄)alkyl.

Embodiment A64

Compounds according to embodiment A63, wherein

-   R₅ is H, alkyl optionally substituted with 1, 2, or 3 groups that    are independently phenylalkoxycarbonyl, —NR₈R₉, halogen, —C(O)NR₈R₉,    alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with    one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl,    alkenyl optionally substituted with alkoxycarbonyl, alkynyl,    —SO₂-alkyl, alkoxy optionally substituted with one trimethylsilyl    group, wherein    -   wherein R₈ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl        C₁-C₄ alkyl and phenyl C₁-C₄ alkanoyl;    -   wherein R₉ is C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl C₁-C₄ alkyl,        pyridyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and        phenyl C₁-C₄ alkanoyl.

Embodiment A65

Compounds according to embodiment A64, wherein

-   R₅ is C₁-C₆ alkyl optionally substituted with 1, 2, or 3 groups that    are independently phenyl C₁-C₄ alkoxycarbonyl, NH₂, mono C₁-C₄    alkylamino, di C₁-C₄ alkylamino, halogen, —C(O)NH₂, —C(O)NH(C₁-C₆    alkyl) wherein the alkyl is optionally substituted with OH, NH₂, or    methoxy, —C(O)N (C₁-C₆ alkyl)(C₁-C₆ alkyl) wherein each alkyl is    optionally substituted with OH, NH₂, or methoxy, C₁-C₄    alkoxycarbonyl, and C₁-C₄ alkanoyl, or-   R₅ is C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₄ alkoxycarbonyl, amino, C₁-C₄    hydroxyalkyl, C₂-C₄ alkenyl optionally substituted with C₁-C₄    alkoxycarbonyl, C₂-C₄ alkynyl, —SO₂—C₁-C₄ alkyl, or C₁-C₄ alkoxy.

Embodiment A66

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

-   R₁ is halogen, NO₂, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or    arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, (C₁-C₄)alkyl,        (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, C₁-C₄ alkoxy, C₁-C₄        alkoxycarbonyl, or spirocyclopropyl;-   R₂ is aryl, heteroaryl, arylalkenyl, arylalkoxy, aryloxyalkyl,    arylalkyl, OH, alkynyl, aryloxy, aryloxyalkyl, arylthioalkoxy,    alkoxy, —OC(O)NH(CH₂)_(n)aryl, —OC(O)N(alkyl)(CH₂)_(n)aryl,    —OSO₂(C₁-C₆)alkyl, —OSO₂aryl, alkyl, alkoxyalkoxy, NR₈R₉, or CO₂H,    wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)CO₂R₃₀, alkoxy, alkoxycarbonyl, CN, NR₆R₇,        haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl,        NR₆R₇—(C₁-C₆ alkyl)-, phenyl, —SO₂-phenyl wherein the phenyl        groups are optionally substituted with 1, 2, or 3 groups that        are independently halogen or NO₂; or —OC(O)NR₆R₇, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkoxyalkyl, alkoxycarbonyl, —SO₂-alkyl, OH,            hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, heteroarylalkyl,            alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein            each of the above is unsubstituted or substituted with 1, 2,            or 3 groups that are independently, halogen, alkoxy,            heterocycloalkyl, OH, SH, C₃-C₆ cycloalkyl, NH₂, NH(alkyl),            N(alkyl)(alkyl), —O-alkanoyl, alkyl, haloalkyl, or            haloalkoxy; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,            hydroxy, hydroxy C₁-C₄ alkyl, or halogen;        -   R at each occurrence is independently H or C₁-C₆ alkyl;        -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups            that are independently OH, SH, halogen, amino,            monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl;-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, arylalkoxy, arylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, carboxaldehyde, CO₂H, alkoxyalkyl,    or alkoxyalkoxy, wherein    -   the aryl portion of arylalkoxy, arylalkyl is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy; and-   R₅ is H, arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl,    -alkyl-5-aryl, -alkyl-SO₂-aryl, —(C₁-C₄)    alkyl-C(O)-heterocycloalkyl, —SO₂-aryl, or heteroaryl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        aryl, arylalkoxy, thioalkoxy, alkoxycarbonyl,        arylalkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,        amidino, hydroxyalkyl, —SO₂alkyl, —SO₂H, —SO₂NR₆R₇, —NR₆R₇,        alkanoyl wherein the alkyl portion is optionally substituted        with OH, halogen or alkoxy, haloalkyl, —(C₁-C₄        alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O,        —O—CH₂CH₂—O—, or haloalkoxy; wherein        -   R₈ at each occurrence is independently hydrogen, alkyl,            alkanoyl, arylalkyl and arylalkanoyl wherein each of the            above is optionally substituted with 1, 2, 3, 4, or 5 groups            that are independently alkyl, alkoxy, alkoxycarbonyl,            halogen, or haloalkyl; and        -   R₉ at each occurrence is independently alkyl, alkanoyl,            arylalkyl cycloalkyl, alkenyl, heteroaryl, cycloalkylalkyl,            arylalkanoyl, —SO₂-phenyl, and aryl wherein each of the            above is optionally substituted with 1, 2, 3, 4, or 5 groups            that are independently alkyl, alkoxy, alkoxycarbonyl,            halogen, or haloalkyl;        -   R₁₅ is H or C₁-C₆ alkyl;        -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or        -   R₁₆, R₁₇, and the nitrogen to which they are attached form a            morpholinyl ring; and        -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆            alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy            C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆            alkyl.            In this embodiment, it is preferred that:            R₆ and R₇ are not simultaneously OH;            R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl);-   when R₂ is OH, R₄ is methyl and R₅ is phenyl, R₁ is not acetyl; and    R₄ and R₅ are not simultaneously hydrogen.

Embodiment A71

Compounds according to embodiment A66 wherein

-   R₁ is halogen, C₁-C₆ alkyl, phenyl, carboxaldehyde, C₁-C₆    hydroxyalkyl, phenyl C₁-C₆ alkoxy, phenyl C₁-C₆ alkyl, CN, C₁-C₆    alkanoyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ haloalkyl,    or phenyl C₁-C₆ alkanoyl,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy or CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy,-   R₂ is phenylalkoxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl,    phenylthio(C₁-C₄)alkoxy, alkoxy, alkenyl, phenethyl,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)(CH₂)_(n)phenyl, alkyl,    alkoxyalkoxy, NR₈R₉, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,    imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino,    tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl,    triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl,    thiazolyl, thienyl, or CO₂H, wherein n is 0, 1, 2, or 3;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, haloalkyl, haloalkoxy, alkyl,        thienyl, pyridyl, or phenyl optionally substituted with 1, 2, or        3 halogens;    -   R₆ and R₇ are independently at each occurrence H, alkyl, alkoxy,        alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl,        —(C₁-C₄)alkyl-CO₂-alkyl, alkanoyl, phenylalkyl, phenylalkoxy, or        phenylalkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, OH, SH, C₃-C₆ cycloalkyl, alkoxy, NH₂, NH(C₁-C₆ alkyl),        N(C₁-C₆ alkyl)(C₁-C₆ alkyl), alkyl, CF₃ or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy        C₁-C₄ alkyl, or halogen;-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, phenylalkyl,    hydroxyalkyl, carboxaldehyde, haloalkyl, alkoxy, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is benzyl, phenethyl, (C₁-C₆)alkyl, phenyl, naphthyl, alkoxy,    piperidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,    isoquinolinyl, tetrahydroisoquinolinyl, indolyl, 1H-indazolyl,    pyridyl, pyrimidyl, pyridazyl, pyrazinyl, piperidinyl(C₁-C₆)alkyl,    pyrrolidinyl(C₁-C₆)alkyl, imidazolidinyl(C₁-C₆)alkyl,    piperazinyl(C₁-C₆)alkyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, tetrahydroisoquinolinyl(C₁-C₆)alkyl,    indolyl(C₁-C₆)alkyl, or 1H-indazolyl(C₁-C₆)alkyl, and wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        hydroxyalkyl, phenylalkoxy, thioalkoxy, alkoxycarbonyl,        phenylalkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, piperazinyl,        morpholinyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₆)alkyl,        —SO₂N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl, or haloalkoxy.

In this embodiment, it is preferred that when R₂ is OH, R₄ is methyl andR₅ is phenyl, R₁ is not acetyl; and

R₄ and R₅ are not simultaneously hydrogen.

Embodiment A72

Compounds according to embodiment A71 wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy,    phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN,    (C₂-C₆)alkanoyl, haloalkyl, or phenylCO—, phenylCH₂CO—,    phenylCH₂CH₂CO—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, haloalkyl, haloalkoxy or        CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy,-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,    phenyloxy(C₁-C₆)alkyl, phenylthio(C₁-C₄)alkoxy, NR₈R₉, (C₁-C₆)alkyl,    alkynyl, phenethyl, —OC(O)N(CH₃)CH₂phenyl, alkoxyalkoxy, pyridyl,    pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl,    piperidinyl, hexahydropyrimidinyl, benzimidazolyl, or thienyl,    wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, CF₃, OCF₃, (C₁-C₄)alkyl, thienyl,        pyridyl, or phenyl optionally substituted with 1, 2, or 3        halogens;    -   R₆ and R₇ are independently at each occurrence H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,        hydroxy(C₁-C₆)alkyl, —(C₁-C₄)alkyl-CO₂-alkyl, (C₁-C₆)alkanoyl,        phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or        phenyl(C₁-C₆)alkanoyl, wherein each of the above is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, (C₁-C₆)alkoxy, NH₂, OH, SH, C₃-C₆        cycloalkyl, (C₁-C₆)alkyl, CF₃ or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or        halogen;-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, benzyloxy, phenethyloxy,    phenpropyloxy, benzyl, phenethyl, phenpropyl, hydroxyalkyl,    halo(C₁-C₄)alkyl, carboxaldehyde, alkoxy, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃ or OCF₃; and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, piperidinyl, pyrrolidinyl, imidazolidinyl,    piperidinyl(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, pyridyl, pyrimidyl, pyridazyl,    pyrazinyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, or pyrazinyl(C₁-C₆)alkyl wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, haloalkyl,        NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, carboxaldehyde, morpholinyl,        SO₂NH₂, SO₂NH(alkyl), SO₂N(alkyl)(alkyl), alkoxy, hydroxyalkyl,        benzyloxy, thioalkoxy, OH, CO₂H, CN, —CO₂(C₁-C₅ alkyl),        phenylalkoxycarbonyl, amidinooxime, amidino, —C(O)NR₆R₇, CF₃,        CF₂CF₃, ClCH₂, or OCF₃.

In this embodiment, it is preferred that when R₂ is OH, R₄ is methyl andR₅ is phenyl, R₁ is not acetyl.

Embodiment A73

Compounds according to embodiment A72 wherein

-   R₁ is halogen, alkyl, carboxaldehyde, hydroxy(C₁-C₄)alkyl,    phenylalkoxy, benzyl, phenethyl, —C(O)CH₃, phenylCO—, or    phenylCH₂CO—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen,        (C₁-C₄)alkyl, (C₁-C₄)alkoxy, nitro, CN, CF₃, or OCF₃;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,    phenyloxy(C₁-C₆)alkyl, phenethyl, NR₈R₉, —S-benzyl, or (C₁-C₆)alkyl,    wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, CF₃, OCF₃, alkyl, thienyl, or        pyridyl;    -   R₆ and R₇ are independently at each occurrence H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,        hydroxy(C₁-C₆)alkyl, —(C₁-C₄)alkyl-CO₂-alkyl, (C₁-C₆)alkanoyl,        phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or        phenyl(C₁-C₆)alkanoyl, wherein each of the above is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, (C₁-C₆)alkoxy, NH₂, OH, SH, C₃-C₆        cycloalkyl, (C₁-C₆)alkyl, CF₃ or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or        halogen;-   R₄ is H, alkyl optionally substituted with one or two groups that    are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, benzyloxy, phenethyloxy,    phenpropyloxy, benzyl, or hydroxyalkyl, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy, alkoxy,        alkyl, nitro, CF₃ or OCF₃; and-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl(C₁-C₆)alkyl,    pyrimidinyl(C₁-C₆)alkyl, or pyridyl(C₁-C₄)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, haloalkyl,        morpholinyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₆),        —SO₂N(C₁-C₆) (C₁-C₆), (C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy,        thio(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, OH, CO₂H, CN,        amidinooxime, amidino, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-,        hydroxyalkyl, CONR₆R₇, CF₃, or OCF₃.

Embodiment A74

Compounds according to embodiment A73 wherein

-   R₁ is halogen, alkyl, carboxaldehyde, or hydroxyalkyl;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,    phenyloxy(C₁-C₆)alkyl, phenethyl, phenylthioalkoxy, or (C₁-C₆)alkyl,    wherein    -   each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently halogen, —(C₁-C₆)alkyl        N(R)—CO₂R₃₀, CF₃, OCF₃, alkyl, thienyl, or pyridyl;-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, benzyloxy, or phenethyloxy,    wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, hydroxy,        (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃ or OCF₃; and-   R₅ is benzyl, phenethyl, (C₁-C₆)alkyl, phenyl, indazolyl, or    pyridyl, wherein each of the above is unsubstituted or substituted    with 1, 2, 3, 4, or 5 groups that are independently (C₁-C₄)alkyl,    halogen, OH, CO₂H, CN, (C₁-C₄)alkoxy, —C(O)pyrrolidine,    —SO₂(C₁-C₆)alkyl, benzyloxy, —CO₂(C₁-C₅ alkyl), amidino,    thio(C₁-C₄)alkoxy, amidinooxime, CF₃, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-,    CONR₆R₇, or OCF₃.

Embodiment A75

Compounds according to embodiment A74 wherein

-   R₁ is chloro, bromo, iodo, methyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl;    and-   R₅ is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each of    which is unsubstituted or substituted with 1, 2, or 3 groups that    are independently alkyl, OH, halogen, alkoxy, NH₂, NH(C₁-C₆)alkyl,    N(C₁-C₆)alkyl(C₁-C₆)alkyl, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, CONR₆R₇, and    amidinooxime; wherein    -   R₆ and R₇ are independently H, C₁-C₄ alkyl, C₁-C₆ alkanoyl,        wherein the alkyl and alkanoyl groups are optionally substituted        with 1, 2, or 3 groups that are independently OH, halogen, or        C₃-C₇ cyclopropyl.

Embodiment A76

Compounds according to embodiment A75 wherein

-   R₂ is benzyloxy, phenethyl, phenyloxy(C₁-C₆)alkyl, or phenethyloxy,    each of which is unsubstituted or substituted with 1, 2, or 3 groups    that are independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, CF₃,    OCF₃, or (C₁-C₄)alkyl.

Embodiment A77

Compounds according to embodiment A66, wherein

-   R₅ is benzyl, phenethyl, thienyl(C₁-C₆ alkyl),    piperidinyl(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, piperazinyl(C₁-C₆)alkyl,    pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl, pyridazyl(C₁-C₆)alkyl,    pyrazinyl(C₁-C₆)alkyl, isoquinolinyl(C₁-C₆)alkyl,    tetrahydroisoquinolinyl(C₁-C₆)alkyl, indolyl(C₁-C₆)alkyl, or    1H-indazolyl(C₁-C₆)alkyl, wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently (C₁-C₆)alkyl, halogen,        (C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, phenyl(C₁-C₆)alkoxy,        (C₁-C₆)thioalkoxy, (C₁-C₆)alkoxycarbonyl,        phenyl(C₁-C₆)alkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, piperazinyl,        morpholinyl, —SO₂ (C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH(C₁-C₆)alkyl,        —SO₂N(C₁-C₆)alkyl(C₁-C₆)alkyl, (C₁-C₄)haloalkyl, —(C₁-C₄        alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O,        —O—CH₂CH₂—O—, or (C₁-C₄)haloalkoxy; wherein        -   R₆ and R₇ are independently at each occurrence H,            (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,            (C₁-C₆)alkoxycarbonyl, (C₁-C₆)hydroxyalkyl,            —(C₁-C₄)alkyl-CO₂—(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,            phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or            phenyl(C₁-C₆)alkanoyl, wherein each of the above is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, (C₁-C₄)alkoxy, NH₂, OH, SH, C₃-C₆            cycloalkyl, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl),            (C₁-C₄)alkyl, CF₃ or OCF₃; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy            C₁-C₄ alkyl, or halogen; and        -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆            alkanoyl, C₁-C₆ hydroxyalkyl, C₃-C₆ alkoxy, C₁-C₆ alkoxy            C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆            alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A78

Compounds according to embodiment A77, wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, or pyridyl; and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, or hydroxy(C₁-C₄)alkyl.

Embodiment A79

Compounds according to embodiment A78, wherein

-   R₅ is benzyl, or phenethyl, wherein each is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl,    phenyl(C₁-C₆)alkoxy, (C₁-C₆)thioalkoxy, (C₁-C₆)alkoxycarbonyl,    phenyl(C₁-C₆)alkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉,    NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇amidino,    piperazinyl, morpholinyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,    —SO₂NH(C₁-C₆)alkyl, —SO₂N(C₁-C₆)alkyl(C₁-C₆)alkyl, (C₁-C₄)haloalkyl,    —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O, —O—CH₂CH₂—O—, or    (C₁-C₄)haloalkoxy; wherein    -   R₆ and R₇ are independently at each occurrence H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,        (C₁-C₆) hydroxyalkyl, —(C₁-C₄)alkyl-CO₂—(C₁-C₆)alkyl,        (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or        phenyl(C₁-C₆)alkanoyl, wherein each of the above is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, (C₁-C₄)alkoxy, NH₂, OH, SH, C₃-C₆        cycloalkyl, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl),        (C₁-C₄)alkyl, CF₃ or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy        C₁-C₄ alkyl, or halogen; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl, amino C₁-C₆ alkyl, or mono or dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A80

Compounds according to embodiment A79, wherein

-   R₅ is benzyl or phenethyl, wherein each is optionally substituted    with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₈R₉, halogen, C₁-C₆ alkoxy,    CO₂H, —(C₁-C₄ alkyl)-CO₂H, C₁-C₆ thioalkoxy, amidinooxime, C₁-C₆    alkoxycarbonyl, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, C₁-C₆    hydroxyalkyl, —(C₁-C₄ alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, OH, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, NR₆R₇—(C₁-C₆ alkyl)-, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈, amidinooxime, —SO₂(C₁-C₆ alkyl), —O—CH₂—O—,    —O—CH₂CH₂—O—, phenyl C₁-C₄ alkoxy, or phenyl; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl) each of which is optionally        substituted with 1, 2, or 3 groups that are independently        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl,        thiomorpholinyl, ring optionally substituted with 1 or 2 groups        that are independently alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or        halogen,    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.-   In this embodiment, it is preferred that R₆ and R₇ are not    simultaneously OH; and-   R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A81

Compounds according to embodiment A80, wherein

-   R₅ is benzyl or phenethyl, wherein each is optionally substituted    with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, halogen, C₁-C₆ alkoxy, CO₂H,    —(C₁-C₄ alkyl)-CO₂H, C₁-C₆ thioalkoxy, amidinooxime, C₁-C₆    alkoxycarbonyl, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, C₁-C₆    hydroxyalkyl, —(C₁-C₄ alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, OH, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, NR₆R₇—(C₁-C₆ alkyl)-, NR₈R₉, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈, amidinooxime, —SO₂(C₁-C₆ alkyl), —O—CH₂—O—,    —O—CH₂CH₂—O—, phenyl C₁-C₄ alkoxy, or phenyl; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl) each of which is optionally        substituted with 1, 2, or 3 groups that are independently        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃; and    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A82

Compounds according to embodiment A81, wherein

-   R₅ is benzyl which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, halogen, C₁-C₄ alkoxy, CO₂H, C₁-C₄ thioalkoxy,    C₁-C₄ alkoxycarbonyl, C₁-C₆ hydroxyalkyl, CN, OH, NR₆R₇—(C₁-C₆    alkyl)-, NR₈R₉, —SO₂(C₁-C₆ alkyl), or benzyloxy; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl) each of which is optionally        substituted with 1, 2, or 3 groups that are independently        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A83

Compounds according to embodiment A82, wherein

-   R₅ is benzyl which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, halogen, C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, C₁-C₄    alkoxycarbonyl, C₁-C₆ hydroxyalkyl, CN, NR₈R₉, or NR₆R₇—(C₁-C₆    alkyl)-; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, or C₁-C₄        alkoxy C₁-C₄ alkyl each of which is optionally substituted with        1, 2, or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH.

Embodiment A84

Compounds according to embodiment A83, wherein

-   the R₅ group is disubstituted with two groups that are meta to each    other.

Embodiment A86

Compounds according to embodiment A80, wherein

-   R₅ is benzyl which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, halogen, C₁-C₄    alkoxy, CO₂H, —(C₁-C₄ alkyl)-CO₂H, —(C₁-C₄ alkyl)-C₁-C₆    alkoxycarbonyl, —(C₁-C₄ alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, CF₃,    OCF₃, —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈ amidinooxime, —O—CH₂—O—,    —O—CH₂CH₂—O—, or phenyl; wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₄ alkyl,        amino C₁-C₄ alkyl, NH(C₁-C₄ alkyl)alkyl, N(C₁-C₄ alkyl)(C₁-C₄        alkyl)C₃-C₄ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl,        or OH, each of which is optionally substituted with 1, 2, or 3        groups that are independently halogen, OH, SH, C₃-C₆ cycloalkyl,        C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃; and    -   R₁₈ is C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₄        alkoxy C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or dialkylamino        C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH.

Embodiment A87

Compounds according to embodiment A80, wherein

-   R₅ is benzyl or phenethyl, wherein each is optionally substituted    with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, halogen, C₁-C₆ alkoxy, CO₂H,    —(C₁-C₄ alkyl)-CO₂H, C₁-C₆ thioalkoxy, amidinooxime, C₁-C₆    alkoxycarbonyl, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, C₁-C₆    hydroxyalkyl, —(C₁-C₄ alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, OH, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, NR₈R₉, NR₆R₇—(C₁-C₆ alkyl)-, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈, amidinooxime, SO₂(C₁-C₆ alkyl), —O—CH₂—O—,    —O—CH₂CH₂—O—, phenyl C₁-C₄ alkoxy, or phenyl; wherein    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl,        thiomorpholinyl, ring optionally substituted with 1 or 2 groups        that are independently alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or        halogen,    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A88

Compounds according to embodiment A87, wherein

-   R₅ is benzyl which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇,    —(C₁-C₄alkyl)-C(O)NR₆R₇, halogen, C₁-C₄ alkoxy, CO₂H, C₁-C₄    thioalkoxy, C₁-C₄ alkoxycarbonyl, C₁-C₆ hydroxyalkyl, CN, OH, NR₈R₉,    NR₆R₇—(C₁-C₆ alkyl)-, —SO₂(C₁-C₆ alkyl), or benzyloxy; and wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, or SO₂(C₁-C₆ alkyl), each of which is optionally        substituted with 1, 2, or 3 groups that are independently        halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl,        OH, CF₃, or OCF₃.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A89

Compounds according to embodiment A80, wherein

-   R₅ is benzyl which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl,    —C(O)NR₆R₇—(C₁-C₄alkyl)C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, NR₈R₉,    halogen, C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, C₁-C₄ alkoxycarbonyl, C₁-C₆    hydroxyalkyl, or CN; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, or C₁-C₄        alkoxy C₁-C₄ alkyl, each of which is optionally substituted with        1, 2, or 3 groups that are independently halogen, OH, SH, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH.

Embodiment A90

Compounds according to embodiment A89, wherein

-   the R₅ group is disubstituted with two groups that are meta to each    other.

Embodiment A91

Compounds according to embodiment A78, wherein

-   R₅ is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —NR₆R₇,    NR₆R₇(C₁-C₆ alkyl), NR₈R₉, C₁-C₆ hydroxyalkyl, halogen, C₁-C₄    alkoxy, CO₂H, OH, C₁-C₆ alkoxycarbonyl, carboxaldehyde, C₁-C₄    haloalkyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄    alkyl)-NR₁₅C(O)R₁₈; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),        —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or C₁-C₆ alkanoyl, each of        which is optionally substituted with 1, 2, or 3 groups that are        independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,        C₁-C₄ alkyl, OH, CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen,    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring;    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH.

Embodiment A92

Compounds according to embodiment A91, wherein

-   R₅ is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    —C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), NR₈R₉, C₁-C₆ hydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂H, OH, C₁-C₆ alkoxycarbonyl,    carboxaldehyde, C₁-C₄ haloalkyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇,    —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈; wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),        —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or C₁-C₆ alkanoyl each of which        is optionally substituted with 1, 2, or 3 groups that are        independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,        C₁-C₄ alkyl, OH, CF₃, or OCF₃;    -   R₁₅ is H or C₁-C₆ alkyl;    -   R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or    -   R₁₆, R₁₇, and the nitrogen to which they are attached form a        morpholinyl ring;    -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆        alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆        alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.

Embodiment A93

Compounds according to embodiment A92, wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, or hydroxy(C₁-C₄)alkyl.

Embodiment A94

Compounds according to embodiment A93, wherein

-   R₅ is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄    alkyl)C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl,    halogen, C₁-C₄ alkoxy, CO₂H, OH, C₁-C₆ alkoxycarbonyl,    carboxaldehyde, C₁-C₄ haloalkyl, wherein    -   R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆        alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆        alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy        C₁-C₆ alkyl, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),        —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or C₁-C₆ alkanoyl, each of        which is optionally substituted with 1, 2, or 3 groups that are        independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy,        C₁-C₄ alkyl, OH, CF₃, or OCF₃;

Embodiment A101

Compounds according to embodiment A66, wherein

-   R₅ is thienyl(C₁-C₆ alkyl), piperidinyl(C₁-C₆)alkyl,    pyrrolidinyl(C₁-C₆)alkyl, imidazolidinyl(C₁-C₆)alkyl,    piperazinyl(C₁-C₆)alkyl, pyridyl(C₁-C₆)alkyl, pyrimidyl(C₁-C₆)alkyl,    pyridazyl(C₁-C₆)alkyl, pyrazinyl(C₁-C₆)alkyl,    isoquinolinyl(C₁-C₆)alkyl, tetrahydroisoquinolinyl(C₁-C₆)alkyl,    indolyl(C₁-C₆)alkyl, 1H-indazolyl(C₁-C₆)alkyl,    dihydroindolonyl(C₁-C₆ alkyl), indolinyl(C₁-C₆ alkyl),    dihydroisoindolyl(C₁-C₆ alkyl), dihydrobenzimdazolyl(C₁-C₆ alkyl),    or dihydrobenzoimidazolonyl(C₁-C₆ alkyl), wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently (C₁-C₆)alkyl, halogen,        (C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, phenyl(C₁-C₆)alkoxy,        (C₁-C₆)thioalkoxy, (C₁-C₆)alkoxycarbonyl,        phenyl(C₁-C₆)alkoxycarbonyl, OH, CO₂H, CN, amidinooxime, NR₈R₉,        NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,        amidino, piperazinyl, morpholinyl, —SO₂(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH(C₁-C₆)alkyl, —SO₂N(C₁-C₆)alkyl(C₁-C₆)alkyl,        (C₁-C₄)haloalkyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, —(C₁-C₄        alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O, —O—CH₂CH₂—O—, or        (C₁-C₄)haloalkoxy; wherein        -   R₆ and R₇ are independently at each occurrence H,            (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,            (C₁-C₆)alkoxycarbonyl, (C₁-C₆) hydroxyalkyl,            —(C₁-C₄)alkyl-CO₂—(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,            phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy, or            phenyl(C₁-C₆)alkanoyl, wherein each of the above is            unsubstituted or substituted with 1, 2, or 3 groups that are            independently, halogen, (C₁-C₄)alkoxy, OH, SH, C₃-C₆            cycloalkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆            alkyl)(C₁-C₄)alkyl, CF₃ or OCF₃; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy            C₁-C₄ alkyl, or halogen; and        -   R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆            alkanoyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy            C₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆            alkyl.

In this embodiment, it is preferred that R₆ and R₇ are notsimultaneously OH; and

R₆ and R₇ are not simultaneously —SO₂(C₁-C₆ alkyl).

Embodiment A102

Compounds according to embodiment A101, wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl optionally substituted with one or two groups    that are independently CO₂H, —CO₂alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)(C₁-C₆)alkoxy, or —NR₆R₇, or hydroxy(C₁-C₄)alkyl.

Embodiment A103

Compounds according to embodiment A102, wherein

-   R₅ is thienyl(C₁-C₆ alkyl), indolyl(C₁-C₆ alkyl), pyridinyl(C₁-C₆    alkyl), piperazinyl(C₁-C₆ alkyl), or pyrazinyl(C₁-C₆ alkyl) each of    which is optionally substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, halogen, —C(O)NR₆R₇,    —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₆ alkoxycarbonyl, —NR₆R₇, NR₆R₇—(C₁-C₆    alkyl)-, haloalkyl, C₁-C₆ alkanoyl,    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A104

Compounds according to embodiment A103, wherein

-   R₅ is thienyl(C₁-C₆ alkyl), indolyl(C₁-C₆ alkyl), pyridinyl(C₁-C₆    alkyl), piperazinyl(C₁-C₆ alkyl), or pyrazinyl(C₁-C₆ alkyl).

Embodiment A105

Compounds according to embodiment A103, wherein

-   R₄ is H, methyl, ethyl, or —CH₂OH;-   R₅ is pyridinyl(C₁-C₆ alkyl), or pyrazinyl(C₁-C₆ alkyl) each of    which is optionally substituted with 1, 2, or 3 groups that are    independently C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, halogen, —C(O)NR₆R₇,    —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₆ alkoxycarbonyl, —NR₆R₇NR₆R₇—(C₁-C₆    alkyl)-, CF₃, C₁-C₆ alkanoyl, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;    -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A106

Compounds according to embodiment A105, wherein

-   R₄ is H, alkyl substituted with one or two groups that are    independently CO₂H, —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇.

Embodiment A112

Compounds according to embodiment 16, wherein

-   R₁ is halogen, or methyl;-   R₂ is benzyloxy, which is optionally substituted with 1, 2, 3, or 4    groups that are independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀,    CF₃, OCF₃, or (C₁-C₄)alkyl; and-   R₄ is H, methyl, ethyl, —CH₂OH, —CH₂CO₂—(C₁-C₄ alkyl), or C₂    hydroxyalkyl.

Embodiment A113

Compounds according to any one of embodiments A85, A95, A97, A98, A99,A100, 16 or 17, wherein

-   R₁ is halogen, or methyl;-   R₂ is benzyloxy, which is optionally substituted with 1, 2, 3, or 4    groups that are independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀,    CF₃, OCF₃, or (C₁-C₄)alkyl; and-   R₄ is alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇.

Embodiment A114

Compounds according to embodiment A66, wherein

-   R₅ is isoquinolinyl(C₁-C₆ alkyl), tetrahydroisoquinolinyl(C₁-C₆    alkyl), 1H-indazolyl(C₁-C₆ alkyl), dihydroindolonyl(C₁-C₆ alkyl),    indolinyl(C₁-C₆ alkyl), dihydroisoindolyl(C₁-C₆ alkyl),    dihydrobenzimdazolyl(C₁-C₆ alkyl), dihydrobenzoimidazolonyl(C₁-C₆    alkyl), each of which is unsubstituted or substituted with 1, 2, or    3 groups that are independently alkyl, alkoxy, halogen, C₁-C₆    alkoxycarbonyl, alkanoyl optionally substituted with 1 or 2 groups    that are independently selected from the group consisting of OH,    NH₂, NH(C₁-C₆ alkyl), and N(C₁-C₆ alkyl) (C₁-C₆ alkyl), —C(O)NR₆R₇,    —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇, —(C₁-C₆ alkyl)-, —NR₆R₇, or SO₂H;    or-   piperidinyl C₁-C₄ alkyl optionally substituted with 1, 2, or 3    groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, or    —NR₆R₇, or C₁-C₆ alkoxycarbonyl.

Embodiment A115

Compounds according to embodiment A114, wherein

-   R₅ is isoquinolinyl(C₁-C₄ alkyl), piperidinyl C₁-C₄ alkyl,    tetrahydroisoquinolinyl(C₁-C₄ alkyl), 1H-indazolyl(C₁-C₄ alkyl),    dihydroindolonyl(C₁-C₄ alkyl), indolinyl(C₁-C₄ alkyl),    dihydroisoindolyl(C₁-C₄ alkyl) dihydrobenzimdazolyl(C₁-C₄ alkyl), or    dihydrobenzoimidazolonyl(C₁-C₄ alkyl).

Embodiment A116

Compounds according to embodiment A114, wherein

-   R₅ is piperidinyl C₁-C₄ alkyl optionally substituted with 1, 2, or 3    groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, or    C₁-C₆ alkoxycarbonyl.

Embodiment A117

Compounds according to embodiment A66, wherein

-   R₅ is pyrimidyl, indolinyl, indolyl, 1H-isoindolyl, isoquinolinyl,    tetrahydroisoquinolinyl, benzimidazolyl, dihydro-1H-benzimidazolyl,    pyrrolyl, imidazolyl, or each of which is optionally substituted    with 1, 2, or 3 groups independently selected from the group    consisting of    -   C₁-C₆ alkoxycarbonyl, C₁-C₄ thioalkoxy, each of which is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆        alkyl)-, —NR₆R₇, alkyl, alkoxy, halogen, C₁-C₆ alkoxycarbonyl,        or alkanoyl optionally substituted with 1 or 2 groups that are        independently selected from the group consisting of OH, NH₂,        NH(C₁-C₆ alkyl), and N(C₁-C₆ alkyl)(C₁-C₆ alkyl), and SO₂H; or    -   pyridyl, pyrazolyl, optionally substituted with 1, 2, or 3        groups that are independently —C(O)NR₆R₇, —(C₁-C₄        alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —NR₆R₇, C₁-C₄ alkyl,        C₁-C₄ hydroxyalkyl, halogen, C₁-C₆ alkoxycarbonyl, —NR₆R₇,        NR₆R₇—(C₁-C₆ alkyl)-, CF₃, C₁-C₆ alkanoyl, wherein        -   R₆ and R₇ at each occurrence are independently H, C₁-C₆            alkyl optionally substituted with 1, 2, or 3 groups that are            independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆            cycloalkyl, OH, SH, or C₁-C₄ alkoxy;        -   or        -   R₆, R₇, and the nitrogen to which they are attached form a            piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl            ring optionally substituted with 1 or 2 groups that are            independently alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or            halogen.

Embodiment A118

Compounds according to embodiment A117, wherein

-   R₅ is pyrimidyl, pyrrolyl, imidazolyl, or pyrazolyl, each of which    is optionally substituted with 1, 2, or 3 groups independently    selected from C₁-C₆ alkoxycarbonyl, C₁-C₄ thioalkoxy, each of which    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently    -   alkyl, alkoxy, halogen, C₁-C₆ alkoxycarbonyl, —C(O)NR₆R₇,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, or —NR₆R₇, or        C₁-C₄ alkanoyl optionally substituted with 1 or 2 groups that        are independently selected from the group consisting of OH, NH₂,        NH(C₁-C₆ alkyl), and N(C₁-C₆ alkyl)(C₁-C₆ alkyl), or SO₂H.

Embodiment A119

Compounds according to embodiment A117, wherein

-   R₅ is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3    groups that are independently C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,    halogen, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-,    or —NR₆R₇, C₁-C₆ alkoxycarbonyl, —NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, CF₃,    C₁-C₆ alkanoyl, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;        -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A120

Compounds according to embodiment A119, wherein

-   R₅ is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3    groups that are independently C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,    halogen, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-,    —NR₆R₇, C₁-C₆ alkoxycarbonyl, CF₃, C₁-C₆ alkanoyl, wherein-   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl    optionally substituted with 1, 2, or 3 groups that are independently    C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl, OH, SH, or C₁-C₄    alkoxy.

Embodiment A121

Compounds according to embodiment A119, wherein

-   R₅ is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3    groups that are independently C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,    halogen, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-,    —NR₆R₇, C₁-C₆ alkoxycarbonyl, CF₃, C₁-C₆ alkanoyl, wherein    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A122

Compounds according to any one of embodiments A114, A115, A116, or A117wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇ (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, hydroxy(C₁-C₄)alkyl.

Embodiment A123

Compounds according to embodiment A66, wherein

-   R₅ is C₁-C₆ alkyl optionally substituted with 1 or 2, groups that    are independently C₁-C₄ alkoxycarbonyl, or halogen, or-   R₅ is C₁-C₆ alkoxy, ethyl, methyl, cyclopropylmethyl, cycloalkyl, or    alkynyl, or-   R₅ is C₂-C₆ alkenyl optionally substituted with C₁-C₄ alkoxycarbonyl    or cyclohexyl.

Embodiment A124

Compounds according to embodiment A123, wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde;-   R₂ is benzyloxy, OH, phenyloxy, phenyloxy(C₁-C₆)alkyl, or    phenyl(C₁-C₄)thioalkoxy, wherein each of the above is optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, NR₆R₇, (C₁-C₄)haloalkyl,    (C₁-C₄)haloalkoxy, (C₁-C₆)alkyl, pyridyl, or NR₆R₇—(C₁-C₆ alkyl)-;    and-   R₄ is H, (C₁-C₄)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, hydroxy(C₁-C₄)alkyl; wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl        optionally substituted with 1, 2, or 3 groups that are        independently C₁-C₄ alkoxycarbonyl, halogen, C₃-C₆ cycloalkyl,        OH, SH, or C₁-C₄ alkoxy;        -   or    -   R₆, R₇, and the nitrogen to which they are attached form a        piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring        optionally substituted with 1 or 2 groups that are independently        alkyl, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A125

Compounds according to embodiment A124, wherein

-   R₅ is C₁-C₆ alkyl optionally substituted with 1 or 2, groups that    are independently C₁-C₄ alkoxycarbonyl, or halogen, or-   R₅ is C₁-C₄ alkoxy, ethyl, methyl, cyclopropylmethyl, cyclohexyl,    cyclopentyl, C₂-C₆ alkynyl, or-   R₅ is C₂-C₆ alkenyl optionally substituted with C₁-C₄ alkoxycarbonyl    or cyclohexyl.

Embodiment A126

Compounds according to embodiment A66, wherein

-   R₂ is phenylalkynyl, —OC(O)NH(CH₂)_(n)aryl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, —OSO₂(C₁-C₆)alkyl, —OSO₂aryl, or NR₈R₉,    wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, alkoxy, alkoxycarbonyl, CN, NR₆R₇,        haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl,        NR₆R₇—(C₁-C₆ alkyl)-, phenyl, —SO₂-phenyl wherein the phenyl        groups are optionally substituted with 1, 2, or 3 groups that        are independently halogen or NO₂; or —OC(O)NR₆R₇, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkoxyalkyl, alkoxycarbonyl, —SO₂-alkyl, OH,            hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, heteroarylalkyl,            alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein            each of the above is unsubstituted or substituted with 1, 2,            or 3 groups that are independently, halogen, alkoxy,            heterocycloalkyl, OH, NH₂, C₃-C₆ cycloalkyl, NH(alkyl),            N(alkyl)(alkyl), —O-alkanoyl, alkyl, C₁-C₄ haloalkyl, or            C₁-C₄ haloalkoxy; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or            piperazinyl ring which is optionally substituted with 1 or 2            groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,            hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A127

Compounds according to embodiment A126, wherein

-   R₁ is halogen, methyl, ethyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or    carboxaldehyde; and-   R₄ is H, (C₁-C₄)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, —NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, or    hydroxy(C₁-C₄)alkyl.

Embodiment A128

Compounds according to embodiment A127, wherein

-   R₅ is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃,    OCF₃, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —NR₆R₇, or    C(O)NR₆R₇, wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl        C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH, C₃-C₆ cycloalkyl,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen; or-   R₅ is benzyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CN, CF₃,    OCF₃, —(C₁-C₄ alkyl)-C(O)NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —NR₆R₇, or    C(O)NR₆R₇

Embodiment A129

Compounds according to embodiment A128, wherein

-   R₂ is NR₈R₉, or NR₈R₉—(C₁-C₄ alkyl)-; wherein    -   R₈ at each occurrence is independently hydrogen, C₁-C₆ alkyl,        C₁-C₆ alkanoyl, phenyl(C₁-C₆)alkyl or phenyl(C₁-C₆)alkanoyl        wherein each of the above is optionally substituted with 1, 2,        3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ alkoxycarbonyl, halogen, or C₁-C₄ haloalkyl; and    -   R₉ at each occurrence is independently C₁-C₆ alkyl, C₁-C₆        alkanoyl, phenyl(C₁-C₆)alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl,        pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, C₃-C₇        cycloalkyl(C₁-C₆)alkyl, phenyl(C₁-C₆) alkanoyl, SO₂-phenyl, and        phenyl wherein each of the above is optionally substituted with        1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, halogen, or C₁-C₄ haloalkyl.

Embodiment A130

Compounds according to embodiment A129, wherein

R₈ is H.

Embodiment A131

Compounds according to embodiment A130, wherein

-   R₂ is —NH-benzyl option substituted with 1, 2, or 3 groups that are    independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃,    or-   R₂ is —NH—C(O)phenyl, wherein the phenyl group is optionally    substituted with 1, 2, or 3 groups that are independently halogen,    C₁-C₄ alkyl, or C₁-C₄ alkoxy; or-   R₂ is —NH-allyl.

Embodiment A132

Compounds according to embodiment A131, wherein

-   R₁ is chloro, bromo, iodo, or methyl; and-   R₅ is benzyl optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, —NR₆R₇, C₁-C₆ alkyl, C₁-C₆ alkoxy, CN, CF₃,    OCF₃, or C(O)NR₆R₇.

Embodiment A133

Compounds according to embodiment A131, wherein

-   R₁ is chloro, bromo, iodo, or methyl; and-   R₅ is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently halogen, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, —NR₆R₇, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃,    or C(O)NR₆R₇.

Embodiment A134

A compound of the formula

or pharmaceutically acceptable salts thereof, wherein

-   -   R₅ is

wherein

-   X₁, X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) at are independently    selected from —C(O)NR₆R₇, —NR₆R₇, hydroxy(C₁-C₄)alkyl, H, OH,    halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl,    C₃-C₇ cycloalkyl, NR₆R₇—(C₁-C₆ alkyl)-, —CO₂—(C₁-C₆)alkyl,    N(R)C(O)NR₆R₇, —N(R)C(O)—(C₁-C₆)alkoxy, CO₂H—(C₁-C₆ alkyl)-, or    —SO₂NR₆R₇; wherein the heteroaryl and heterocycloalkyl groups are    optionally substituted with —NR₆R₇, —C(O)NR₆R₇, NR₆R₇—(C₁-C₆    alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen;    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, C₁-C₆ thiohydroxyalkyl,        —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,        benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, wherein        each of the above is unsubstituted or substituted with 1, 2, or        3 groups that are independently, halogen, C₃-C₆ cycloalkyl,        C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,        piperazinyl C₁-C₆ alkyl, OH, SH, NH₂, NH(alkyl),        N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃;        or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen;

R at each occurrence is independently H or C₁-C₆ alkyl; and

-   Y, Y₁, Y₂, Y₃, and Y₄ are independently selected from H, halogen,    alkyl, carboxaldehyde, hydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl,    alkoxy, alkoxyalkyl, haloalkyl, and carboxyl.

Embodiment A135

Compounds according to embodiment A134, wherein

-   Y₂, Y₄, and Y are independently halogen; and-   Y₁ and Y₃ are both hydrogen.

Embodiment A136

Compounds according to embodiment A135, wherein

-   X₁ is H, methyl, —NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, C₁-C₆    hydroxyalkyl, or —(C₁-C₄ alkyl)-morpholinyl.

Embodiment A137

Compounds according to embodiment A136, wherein

-   X_(a) and X_(e) are independently halogen, is NH₂, NH(C₁-C₆ alkyl),    N(C₁-C₆ alkyl)(C₁-C₆ alkyl) or methyl.

Embodiment A138

Compounds according to embodiment A137, wherein

X_(b) or X_(c) is —NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, SO₂NR₆R₇, orhalogen; wherein

-   -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A139

Compounds according to embodiment A138, wherein

-   R₆, R₇, and the nitrogen to which they are attached form a    morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or    piperazinyl ring which is optionally substituted with 1 or 2 groups    that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy    C₁-C₄ alkyl, or halogen.

Embodiment A140

Compounds according to embodiment A138, wherein

-   R₆, R₇, and the nitrogen to which they are attached form a    piperazinyl ring which is optionally substituted with 1 or 2 groups    that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy    C₁-C₄ alkyl, or halogen

Embodiment A141

Compounds according to embodiment A138, wherein

-   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₆    alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, OH, C₁-C₆    hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆    alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl,    wherein each of the above is unsubstituted or substituted with 1, 2,    or 3 groups that are independently, halogen, C₃-C₆ cycloalkyl, C₁-C₆    alkoxy, piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl,    piperazinyl C₁-C₆ alkyl, OH, NH₂, NH(alkyl), N(alkyl)(alkyl),    —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃.

Embodiment A142

Compounds according to embodiment A138, wherein

-   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₆    hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, or C₁-C₆    alkanoyl, wherein each of the above is optionally substituted with    1, 2, or 3 groups that are independently OH, SH, halogen, or C₃-C₆    cycloalkyl.

Embodiment A143

Compounds according to embodiment A137, wherein

-   X_(a) and X_(e) are independently fluoro, chloro, or methyl; and-   X_(c) is hydrogen or halogen.

Embodiment A144

Compounds according to embodiment A137, wherein

-   X_(e) is halogen;-   X_(e) is NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆ alkyl);-   X_(b) and X_(d) are both hydrogen.

Embodiment A145

Compounds according to embodiment A144, wherein

-   X_(c) is —NR₆R₇, NR₆R₇C₁-C₆ alkyl, —SO₂NR₆R₇, or halogen; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A146

Compounds according to embodiment A145, wherein

-   X_(c) is fluoro, chloro, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆    alkyl), SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆    alkyl), or piperazinyl, wherein the piperazinyl group is optionally    substituted with 1 or 2 groups that are independently C₁-C₄ alkyl,    C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A147

Compounds according to either embodiment A137 or A144, wherein

-   X_(c) is —C(O)NR₆R₇, —(C₁-C₆ alkyl)-C(O)NR₆R₇, NR₆R₇, or    NR₆R₇—(C₁-C₆ alkyl)-; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A148

Compounds according to embodiment A147, wherein

-   R₆ is hydrogen; and-   R₇ is C₁-C₆ alkyl or C₁-C₆ alkanoyl, each of which is optionally    substituted with 1, 2, or 3 groups that are independently NH₂,    NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, SH, cyclopropyl,    or C₁-C₄ alkoxy.

Embodiment A148a

Compounds according to embodiment A148, wherein

-   R₇ is C₁-C₆ alkanoyl optionally substituted with 1, 2, or 3 groups    that are independently OH, cyclopropyl, or NH₂.

Embodiment A149

Compounds according to embodiment A135, wherein

-   X_(a) is hydrogen;-   X_(b), X_(c), or X_(d) is —C(O)NR₆R₇, —(C₁-C₆ alkyl)-C(O)NR₆R₇,    NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)- or —CO₂—(C₁-C₆)alkyl; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂ alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄        alkyl, or halogen; and-   X_(e) is hydrogen, methyl, C₁-C₂ alkoxy, or halogen.

Embodiment A150

Compounds according to embodiment A149, wherein

-   X_(b) is NR₆R₇, or NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇ or    —CO₂—(C₁-C₆)alkyl; wherein-   R₆ is hydrogen or C₁-C₄ alkyl;-   R₇ is OH, C₁-C₆ alkyl or C₁-C₆ alkanoyl, wherein the alkyl and    alkanoyl groups substituted with 1, 2, or 3 groups that are    independently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl),    C₃-C₆ cycloalkyl, OH, or C₁-C₄ alkoxy.

Embodiment A151

Compounds according to embodiment A137, wherein

-   X_(a) is halogen;-   X_(b) is NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, or    —CO₂—(C₁-C₆)alkyl;-   X_(c) is NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, halogen,    —CO₂—(C₁-C₆)alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆    alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆    alkyl), or piperazinyl, wherein the piperazinyl group is optionally    substituted with 1 or 2 groups that are independently C₁-C₄ alkyl,    C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, or halogen;-   X_(d) is hydrogen;-   X_(e) is H, methyl, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)(C₁-C₆    alkyl).

Embodiment A152

Compounds according to embodiment A135, wherein

-   X₁, X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) are independently    selected from H, OH, halogen, CF₃, alkyl, OCF₃, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,    piperidinyl, piperazinyl, or C₃-C₇ cycloalkyl, wherein each of the    above is optionally substituted with —NR₆R₇, —C(O)NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen.

Embodiment A153

Compounds according to embodiment A152, wherein at least three of X₁,X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) are hydrogen.

Embodiment A154

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

-   R₁ is alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl,    hydroxyalkyl, or carboxaldehyde, wherein    -   the aryl portion of arylalkyl, and arylalkanoyl is unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,        haloalkyl, haloalkoxy or CO₂H;    -   the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl,        alkoxyalkyl and arylalkanoyl groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, ethoxy or spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, phenyloxy(C₁-C₆)alkyl, OH, halogen,    arylthioalkoxy, alkoxy, —OC(O)NH(CH₂)_(n)aryl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, alkyl, alkoxyalkoxy, dialkylamino,    pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl,    tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl,    pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,    hexahydropyrimidinyl, thiazolyl, thienyl, or CO₂H, wherein n is 0,    1, 2, 3, 4, 5 or 6;    -   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,        —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl)(CH₂)_(n)aryl or the        heteroaryl and heterocycloalkyl groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, haloalkyl, heteroaryl,        heteroarylalkyl, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —OC(O)NR₆R₇,        wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl,            wherein each of the above is unsubstituted or substituted            with 1, 2, or 3 groups that are independently, halogen, OH,            SH, C₃-C₆ cycloalkyl, alkoxy, alkyl, haloalkyl, or            haloalkoxy; or        -   R₆, R₇, and the nitrogen to which they are attached form a            morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,            thiomorpholinyl S,S-dioxide, piperidinyl, or piperazinyl            ring which is optionally substituted with 1 or 2 groups that            are independently C₁-C₄ alkyl, alkoxycarbonyl, hydroxyl,            hydroxyalkyl, or halogen;        -   R at each occurrence is independently H or C₁-C₆ alkyl;        -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups            that are independently OH, SH, halogen, amino,            monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl;-   R₃ is halogen, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,    —OC(O)NH(CH₂)_(n)aryl, arylalkoxy, —OC(O)N(alkyl)(CH₂)_(n)aryl,    aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, or alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,        —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, alkyl substituted with one group selected from CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, and —NR₆R₇, arylalkoxy, arylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the aryl portion of arylalkoxy, arylalkyl is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl,    wherein    -   each of the above is unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently alkyl, halogen, alkoxy,        arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,        CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇,        amidino, haloalkyl, or haloalkoxy.

Embodiment A160

Compounds according to embodiment A154 wherein

-   R₁ is halogen, (C₁-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,    naphthyl(C₁-C₆)alkanoyl, naphthyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl,    alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein    -   the phenyl and naphthyl portions of the above are unsubstituted        or substituted with 1, 2, 3, 4, or 5 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,        CF₃, OCF₃ or CO₂H;    -   the alkyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy.-   R₂ is phenylalkoxy, aryloxy, phenyloxy(C₁-C₆)alkyl, OH, halogen,    phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)(CH₂)_(n)phenyl, pyridyl,    pyrimidyl, pyridazyl, pyrazolyl, or thienyl, wherein    -   n is 0, 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, 3,        4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, halo(C₁-C₄)alkyl, or thienyl;-   R₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,    phenyl(C₁-C₆)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy,    arylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, or    alkyl, wherein    -   the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl,        aryloxycarbonyl, arylalkyl,—OC(O)NH(CH₂)_(n)aryl,arylthioalkoxy,        arylalkoxy, and —OC(O)N(alkyl)(CH₂)_(n)aryl, are unsubstituted        or substituted with 1, 2, or 3 groups that are independently,        halogen, alkoxy, alkyl, CF₃, or OCF₃,        wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, (C₁-C₆)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy,    phenyl(C₁-C₆)alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or    alkoxyalkoxy, wherein    -   the phenyl portion of the above groups are unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, or OCF₃.-   R₅ is phenyl(C₁-C₆)alkyl, (C₁-C₆)alkyl, phenyl, naphthyl, pyridyl,    (C₁-C₆)alkoxy, piperidinyl(C₁-C₆)alkyl, pyrrolyl(C₁-C₆)alkyl,    imidazolidinyl(C₁-C₆)alkyl, pyrazolyl(C₁-C₆)alkyl,    imidazolyl(C₁-C₆)alkyl, tetrahydropyridinyl(C₁-C₆)alkyl,    thienyl(C₁-C₆)alkyl, phenylthio(C₁-C₆)alkyl, or pyridyl(C₁-C₆)alkyl,    wherein each of the above is unsubstituted or substituted with 1, 2,    or 3 groups that are independently (C₁-C₄)alkyl, fluoro, chloro,    bromo, (C₁-C₄)alkoxy, phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy,    (C₁-C₄)alkoxycarbonyl, phenyl(C₁-C₄)alkoxycarbonyl, CO₂H, CN,    amidinooxime, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, CF₃,    —CF₂CF₃, OCF₃ or OCF₂CF₃.

Embodiment A161

Compounds according to embodiment A160 wherein

-   R₁ is halogen, (C₁-C₄)alkanoyl, phenyl(C₁-C₄)alkanoyl, benzyl,    phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;

the alkyl portion of the above groups are unsubstituted or substitutedwith 1, 2, or 3 groups that are independently halogen, methoxy, orethoxy;

-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,    phenyloxy, phenyloxy(C₁-C₆)alkyl, OH, halogen, phenylthioalkoxy,    alkoxy, alkyl, alkoxyalkoxy, wherein    -   n is 0, 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, or        3, groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, halo(C₁-C₄)alkyl, or thienyl;-   R₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,    phenyl(C₁-C₆)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy,    phenylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇, NR₆R₇C₁-C₆ alkyl, or alkyl,    wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently, halogen, alkoxy,        (C₁-C₄)alkyl, CF₃, or OCF₃,-   R₄ is H, (C₁-C₆)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, benzyl,    phenethyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the phenyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃, or        OCF₃.-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C₁-C₆)alkyl,    phenyl, or pyridyl, wherein each of the above is unsubstituted or    substituted with 1, 2, or 3 groups that are independently    (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy,    phenyl(C₁-C₄)alkoxy, thio(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, CO₂H,    CN, amidinooxime, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino,    CF₃, or OCF₃.

Embodiment A162

Compounds according to embodiment A161 wherein

-   R₁ is bromo, phenyl(C₁-C₄)alkanoyl, benzyl, phenethyl, phenpropyl,    hydroxyalkyl, or carboxaldehyde, wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,    phenyloxy, phenyloxy(C₁-C₆)alkyl, OH, halogen, or phenylthioalkoxy,    wherein    -   n is 0, 1, 2, 3, or 4, and    -   the above groups are unsubstituted or substituted with 1, 2, or        3, groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, halo(C₁-C₄)alkyl, or thienyl;-   R₃ is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl,    phenyl(C₁-C₆)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy,    phenylthioalkoxy, (C₂-C₆)alkenyl, NR₆R₇, NR₆R₇C₁-C₆ alkyl, or alkyl,    wherein    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently, halogen, alkoxy,        (C₁-C₄)alkyl, CF₃, or OCF₃,-   R₄ is H, (C₁-C₁₀)alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, benzyl, or    phenethyl, wherein    -   the phenyl portion of the above groups are unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, nitro, CF₃, or        OCF₃.-   R₅ is benzyl, phenethyl, phenpropyl, (C₁-C₆)alkyl, phenyl, or    pyridyl, wherein each of the above is unsubstituted or substituted    with 1, 2, or 3 groups that are independently (C₁-C₄)alkyl, fluoro,    chloro, bromo, (C₁-C₄)alkoxy, CO₂H, CN, amidinooxime, amidino, CF₃,    OCF₃, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, or —C(O)NR₆R₇; wherein    -   R₆ and R₇ are independently hydrogen, OH, C₁-C₄ alkoxy, C₁-C₆        alkanoyl, or C₁-C₆ alkyl, wherein each of the above is        optionally substituted with 1 or 2 groups that are independently        OH, NH₂, C₃-C₆ cycloalkyl, or halogen; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄        alkyl, or halogen.

Embodiment A163

Compounds of the formula

or pharmaceutically acceptable salts thereof, wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is H, arylthio, —OC(O)NH(CH₂)_(n)aryl, arylalkyl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, or arylthioalkoxy, wherein n is 1, 2,    3, 4, or 5; wherein the aryl groups are optionally substituted with    1, 2, 3, 4, or 5 groups that are independently halogen,    —(C₁-C₆)alkyl-N(R)CO₂R₃₀, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, or OCF₃;    -   R at each occurrence is independently H or C₁-C₆ alkyl;    -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups        that are independently OH, SH, halogen, amino, monoalkylamino,        dialkylamino or C₃-C₆ cycloalkyl;-   R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,    arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,    —OC(O)N(alkyl)(CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,    arylthioalkoxy, alkenyl, NR₆R₇C₁-C₆ alkyl, NR₆R₇ or alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,        —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, arylalkoxy, arylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the aryl portion of arylalkoxy, arylalkyl is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy; and-   R₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,    heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl,    wherein each of the above is unsubstituted or substituted with 1, 2,    3, 4, or 5 groups that are independently alkyl, halogen, alkoxy,    arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO₂H,    CN, amidinooxime, NR₆R₇, NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino,    haloalkyl, or haloalkoxy; wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen.

Embodiment A168

Compounds according to embodiment A163 wherein

-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,    alkoxy, pyridyl(C₁-C₆)alkyl, phenyl(C₁-C₆)thioalkyl, pyrrolyl,    pyrrolyl(C₁-C₆)alkyl, or pyridyl, wherein each of the above is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,    phenyl(C₁-C₆)alkoxy, (C₁-C₆)thioalkoxy, alkoxycarbonyl, CO₂H, CN,    amidinooxime, amidino, CF₃, or OCF₃.

Embodiment A169

Compounds according to embodiment A163 wherein

-   R₁ is H, Cl, Br, (C₁-C₆)alkyl, carboxaldehyde, hydroxy(C₁-C₆)alkyl,    -   wherein the alkyl portion of above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently        halogen, methoxy, or ethoxy-   R₂ is H, phenylthio, —OC(O)NH(CH₂)_(n)aryl, phenylalkyl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, or phenylthio(C₁-C₆)alkoxy, wherein n    is 1, 2, 3, or 4;    -   wherein the aryl groups are optionally substituted with 1, 2, 3,        4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, or        OCF₃;-   R₃ is bromo, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen,        (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or        halo(C₁-C₄)alkoxy,    -   wherein n is 0, 1, 2, 3, or 4;-   R₄ is H, alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, phenylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or wherein    -   the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted        or substituted with 1, 2, or 3 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy-   R₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,    phenyl(C₁-C₆)thioalkyl, pyrrolyl, or pyridyl, wherein each of the    above is unsubstituted or substituted with 1, 2, or 3 groups that    are independently (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, benzyloxy,    (C₁-C₆)thioalkoxy, alkoxycarbonyl, CO₂H, CN, amidinooxime, amidino,    CF₃, or OCF₃;    -   R₆ and R₇ are independently hydrogen, OH, C₁-C₄ alkoxy, C₁-C₆        alkanoyl, or C₁-C₆ alkyl, wherein each of the above is        optionally substituted with 1 or 2 groups that are independently        OH, NH₂, C₃-C₆ cycloalkyl, or halogen; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring        which is optionally substituted with 1 or 2 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄        alkyl, or halogen.

Embodiment A170

Compounds according to embodiment 1

or a pharmaceutically acceptable salt thereof, wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy,    arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl,    -   wherein the aryl portion of arylalkoxy, arylalkyl, and        arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or        5 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO₂H;    -   wherein the alkyl portion of the alkyl, hydroxyalkyl,        arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and        arylalkanoyl groups is unsubstituted or substituted with 1, 2,        or 3 groups that are independently halogen, methoxy, ethoxy or        spirocyclopropyl;-   R₂ is arylalkoxy, aryloxy, aryloxyalkyl, OH, halogen,    arylthioalkoxy, alkoxy, —OC(O)NH(CH₂)_(n)aryl,    —OC(O)N(alkyl)(CH₂)_(n)aryl, alkyl, alkoxyalkoxy, dialkylamino, or    CO₂H, wherein    -   n is 0, 1, 2, 3, 4, 5 or 6;    -   the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,        —OC(O)NH(CH₂)_(n)aryl, and —OC(O)N(alkyl)(CH₂)_(n)aryl or the        heteroaryl and heterocycloalkyl groups is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, haloalkyl, heteroaryl,        heteroarylalkyl, NR₆R₇, NR₆,R₇—(C₁-C₆ alkyl)-, —OC(O)NR₆R₇,        wherein    -   R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,        OH, C₁-C₆ hydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl        C₁-C₆ alkanoyl, wherein each of the above is unsubstituted or        substituted with 1, 2, or 3 groups that are independently,        halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆        alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, SH,        NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl,        CF₃, or OCF₃; or    -   R₆, R₇, and the nitrogen to which they are attached form a        morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or        piperazinyl ring which is optionally substituted with 1 or 2        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        hydroxy, hydroxy C₁-C₄ alkyl, or halogen;    -   R at each occurrence is independently H or C₁-C₆ alkyl;    -   R₃₀ is C₁-C₆ alkyl optionally substituted with 1 or 2 groups        that are independently OH, SH, halogen, amino, monoalkylamino,        dialkylamino or C₃-C₆ cycloalkyl;-   R₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl,    arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,    —OC(O)N(alkyl)(CH₂)_(n)aryl, aryloxy, arylthio, thioalkoxy,    arylthioalkoxy, alkenyl, NR₆R₇C₁-C₆ alkyl, NR₆R₇ or alkyl, wherein    -   the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,        arylalkyl, —OC(O)NH(CH₂)_(n)aryl, arylalkoxy,        —OC(O)N(alkyl)(CH₂)_(n)aryl, and arylthioalkoxy, is        unsubstituted or substituted with 1, 2, or 3 groups that are        independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3, 4, 5, or 6; or-   R₄ is H, alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)(C₁-C₆)alkoxy, or —NR₆R₇, arylalkoxy, arylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the aryl portion of arylalkoxy, arylalkyl is unsubstituted or        substituted with 1, 2, 3, 4, or 5 groups that are independently        halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or        haloalkoxy; and-   R₅ is aryl, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl,    heterocycloalkyl, or heteroaryl, wherein each of the above is    unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are    independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy,    alkoxycarbonyl, arylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.

Embodiment A173

Compounds according to embodiment A170 wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy,    phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN,    alkanoyl, alkoxy, or phenylC(O)—, phenylCH₂C(O)—, or    phenylCH₂CH₂C(O),    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;    -   wherein the above alkyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, methoxy,        or ethoxy;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy,    phenyloxy(C₁-C₆)alkyl, OH, halogen, phenylthioalkoxy, alkyl, alkoxy,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)(CH₂)_(n)phenyl,    dialkylamino, or CO₂H, wherein    -   n is 0, 1, 2, 3, or 4;    -   the above aryl groups are unsubstituted or substituted with 1,        2, 3, 4, or 5 groups that are independently halogen,        —(C₁-C₆)alkyl-N(R)CO₂R₃₀, CF₃, pyridyl, thienyl, NR₆R₇, or        NR₆R₇—(C₁-C₆ alkyl)-, wherein        -   R₆ and R₇ are independently at each occurrence H, alkyl,            alkanoyl, benzyl, or phenylC(O)—, wherein the phenyl portion            of the above is unsubstituted or substituted with 1, 2, or 3            groups that are independently, halogen, OH, C₃-C₆            cycloalkyl, alkoxy, alkyl, CF₃, or OCF₃;-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, —OC(O)NH(CH₂)_(n)phenyl,    phenylalkoxy, —OC(O)N(alkyl)(CH₂)_(n)phenyl, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3, or 4;-   R₄ is H, alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, phenylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl    pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl,    piperidinyl, pyridyl, or thienylalkyl, wherein each of the above is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy,    alkoxycarbonyl, phenylalkoxycarbonyl, CO₂H, CN, amidinooxime, NR₆R₇,    NR₆R₇—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, amidino, haloalkyl, or haloalkoxy.

Embodiment A174

Compounds according to embodiment A173 wherein

-   R₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy,    phenethyloxy, benzyl, phenethyl, CN, (C₁-C₆)alkanoyl, alkoxy, or    phenylC(O)—, or phenylCH₂C(O)—,    -   wherein the above phenyl groups are unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, C₁-C₄        alkyl, C₁-C₄ alkoxy, nitro, CN, CF₃, OCF₃ or CO₂H;-   R₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy,    phenyloxy(C₁-C₆)alkyl, halogen, phenyl(C₁-C₄)thioalkoxy,    —OC(O)NH(CH₂)_(n)phenyl, —OC(O)N(alkyl)(CH₂)_(n)phenyl, or    dialkylamino, wherein    -   n is 0, 1, 2, 3, or 4;    -   the above phenyl groups are unsubstituted or substituted with 1,        2, or 3 groups that are independently halogen, CF₃, NR₆R₇, or        NR₆R₇—(C₁-C₆ alkyl)-, wherein        -   R₆ and R₇ are independently at each occurrence H,            (C₁-C₆)alkyl, acetyl, benzyl, or phenylC(O)—, wherein the            phenyl portion of the above is unsubstituted or substituted            with 1, 2, or 3 groups that are independently, halogen, OH,            cyclopropyl, alkoxy, alkyl, CF₃, or OCF₃;-   R₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,    phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio,    thioalkoxy, phenylthioalkoxy, alkenyl, NR₆R₇ or alkyl, wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently, halogen, alkoxy,        alkyl, haloalkyl, or haloalkoxy,        -   wherein n is 0, 1, 2, 3, or 4;-   R₄ is H, alkyl substituted with one group that is CO₂H,    —CO₂—(C₁-C₆)alkyl, —C(O)NRR, —N(R₃₀)C(O)NRR,    —N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, phenylalkoxy, phenylalkyl,    hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy,    wherein    -   the phenyl portion of the above is unsubstituted or substituted        with 1, 2, or 3 groups that are independently halogen, hydroxy,        alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and-   R₅ is phenyl, phenyl(C₁-C₄)thioalkyl, pyridyl, or    thienyl(C₁-C₄)alkyl, wherein each of the above is unsubstituted or    substituted with 1, 2, or 3 groups that are independently    (C₁-C₄)alkyl, fluoro, chloro, bromo, (C₁-C₄)alkoxy, CN,    amidinooxime, amidino, CF₃, or OCF₃.

Embodiment A175

Compounds according to embodiment A174 wherein

-   R₅ is substituted with at least one group selected from fluoro,    chloro, bromo, and methyl.

In another aspect, the invention provides pharmaceutical compositionscomprising at least one pharmaceutically acceptable carrier, solvent,adjuvant or excipient and a compound of formula I, embodiment A66, orembodiment A154.

The invention further provides pharmaceutical compositions comprising atleast one pharmaceutically acceptable carrier, solvent, adjuvant orexcipient and compounds according to any of the preceding embodiments.

As noted above, the invention encompasses methods of treating a TNFmediated disorder, a p38 kinase mediated disorder, inflammation and/orarthritis in a subject, the method comprising treating a subject havingor susceptible to such disorder or condition with atherapeutically-effective amount of a compound of formula I orembodiment A1.

More specifically, the invention provides methods for treating orpreventing inflammation; arthritis, rheumatoid arthritis,spondylarthropathies, gouty arthritis, osteoarthritis, systemic lupuserthematosus, juvenile arthritis, and other arthritic conditions;neuroinflammation; allergy, Th2 mediated diseases; pain, neuropathicpain; fever; pulmonary disorders, lung inflammation, adult respiratorydistress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD); cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),thrombosis, congestive heart failure, cardiac reperfusion injury, aswell as complications associated with hypertension and/or heart failuresuch as vascular organ damage, restenosis; cardiomyopathy; strokeincluding ischemic and hemorrhagic stroke; reperfusion injury; renalreperfusion injury; ischemia including stroke and brain ischemia, andischemia resulting from cardiac/coronary bypass; neurotrauma and braintrauma including closed head injury; brain edema; neurodegenerativedisorders; liver disease and nephritis; gastrointestinal conditions,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis; ulcerative diseases, gastric ulcers;ophthalmic diseases, retinitis, retinopathies, uveitis, ocularphotophobia, acute injury to the eye tissue and ocular traumas such aspost-traumatic glaucoma, traumatic optic neuropathy, and central retinalartery occlusion (CRAO); periodontal disease; opthalmologicalconditions, retinitis, retinopathies (including diabetic retinopathy),uveitis, ocular photophobia, nonglaucomatous optic nerve atrophy, andage related macular degeneration (ARMD) (including ARMD-atrophic form),corneal graft rejection, ocular neovascularization, retinalneovascularization, neovascularization following injury or infection,retrolental fibroplasias, neovascular glaucoma; glaucoma includingprimary open angle glaucoma (POAG), juvenile onset primary open-angleglaucoma, angle-closure glaucoma, pseudoexfoliative glaucoma, anteriorischemic optic neuropathy (AION), ocular hypertension, Reiger'ssyndrome, normal tension glaucoma, neovascular glaucoma, ocularinflammation and corticosteroid-induced glaucoma; diabetes; diabeticnephropathy; skin-related conditions, psoriasis, eczema, burns,dermatitis, keloid formation, scar tissue formation, angiogenicdisorders; viral and bacterial infections, sepsis, septic shock, gramnegative sepsis, malaria, meningitis, HIV infection, opportunisticinfections, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated complex), pneumonia, herpes virus; myalgias due to infection;influenza; endotoxic shock; toxic shock syndrome; autoimmune disease,graft vs. host reaction and allograft rejections; treatment of boneresorption diseases, osteoporosis; multiple sclerosis; disorders of thefemale reproductive system, endometriosis; hemaginomas, infantilehemagionmas, angiofibroma of the nasopharynx, avascular necrosis ofbone; benign and malignant tumors/neoplasia, cancer, colorectal cancer,brain cancer, bone cancer, epithelial call-derived neoplasia (epithelialcarcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinalcancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer,stomach cancer, colon cancer, liver cancer, bladder cancer, pancreascancer, ovarian cancer, cervical cancer, lung cancer, breast cancer,skin cancer, squamus cell and/or basal cell cancers, prostate cancer,renal cell carcinoma, and other known cancers that affect epithelialcells throughout the body; leukemia; lymphoma; systemic lupuserthrematosis (SLE); angiogenesis including neoplasia; metastasis;central nervous system disorders, central nervous system disordershaving an inflammatory or apoptotic component, Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, spinal cord injury, and peripheral neuropathy; Canine B-CellLymphoma. Compounds of the invention are also useful for preventing theproduction or expression of cyclooxygenase-2, or cyclooxygenase-2activity.

In this aspect, the invention encompasses methods of treating a p38kinase or TNF-alpha mediated disorder comprising administering to apatient in need thereof a therapeutically effective amount of Compoundsaccording to embodiment 1 and at least one pharmaceutically acceptablecarrier, adjuvant, solvent or excipient.

Representative compounds of the invention are:

-   1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-difluorobenzyl)oxy]pyridazin-3(2H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(3 methylbenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoic acid;-   4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin 2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide;-   methyl    4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2(1H)-one;-   4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;-   4-bromo-2-(2,6-dichlorophenyl)-5-{[2-(hydroxymethyl)benzyl]oxy}pyridazin-3(2H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 57

Compounds according to embodiment 1 or embodiment A1, which is

-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-[2-(phenylthio)ethyl]pyridin-2(1H)-one;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-2(1H)-one;-   3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-one    hydrochloride;-   3-bromo-1-(4-methoxybenzyl)-4-phenoxypyridin-2(1H)-one;-   1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-phenylpropyl)pyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one    hydrochloride;-   1-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;-   1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H)-one;-   3-bromo-1-(4-methylbenzyl)-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;-   methyl    4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   4-(benzyloxy)-3-bromo-1-(2-thien-3-ylethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(2-thien-2-ylethyl)pyridin-2(1H)-one;-   1-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide;-   4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   1-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;-   methyl    5-chloro-1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carboxylate;-   3-benzyl-4-hydroxy-1-(2-phenylethyl)pyridin-2(1H)-one;-   5-bromo-1-(2-chloro-6-fluorobenzyl)-3-methylpyridin-2(1H)-one;-   1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   1-benzyl-4-chloro-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   1-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl    methyl(phenyl)carbamate;-   1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-(3-phenylpropyl)pyridin-2(1H)-one;-   1-benzyl-3-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;-   1-benzyl-3-methyl-4-(3-phenylpropyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)-3-methylpyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;-   1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;-   3-acetyl-4-hydroxy-6-methyl-1-[choro]phenylpyridin-2(1H)-one;-   6-(benzyloxy)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;-   3-benzoyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;-   3-benzyl-6-(benzyloxy)-1-methylpyridin-2(1H)-one;-   1-benzyl-4-hydroxypyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)pyridin-2(1H)-one-   4-amino-1-benzylpyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;-   1-benzyl-4-hydroxypyridin-2(1H)-one;-   1-benzyl-2 oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate;    or a pharmaceutically acceptable thereof.

Embodiment 58

Compounds according to embodiment 1 or embodiment A1, which is

-   4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   methyl 4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   methyl-4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one;-   1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    4-bromobenzenesulfonate;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    4-bromobenzenesulfonate;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-Benzyl 4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;-   4-[(2,6-dichlorobenzyl)oxy]pyridine-1-oxide;-   4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide;-   1-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one;-   1-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;-   1-Benzyl-4-[benzylthio]-3-bromopyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one;-   3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one;-   3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one;-   1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl    trifluoromethanesulfonate;-   1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;-   1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    trifluoromethanesulfonate;-   3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one;-   3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;-   1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl    trifluoromethanesulfonate;-   3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one;-   4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;-   4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one;

or a pharmaceutically acceptable salt thereof.

Embodiment 59

Compounds according to embodiment 1 or embodiment A1, which is

-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-flurobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]piperidin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;

or a pharmaceutically acceptable salt thereof.

Embodiment 60

Compounds according to embodiment 1, which is

-   1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-2,3-dihydro-1H-indol-5-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-2,3-dihydro-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]indoline-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]pyridin-2(1H)-one;-   1-(1-acetyl-1H-indol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-1H-indol-5-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-1H-indol-5-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1](3-hydroxypropanoyl)-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(3-hydroxy-3-methylbutanoyl)-1H-indol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-indole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-1H-indol-5-yl]pyridin-2(1H)-one;-   1-(2-acetyl-2,3-dihydro-1H-isoindol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2-glycoloyl-2,3-dihydro-1H-isoindol-5-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-isoindol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(N-methylglycyl)-2,3-dihydro-1H-isoindol-5-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxypropanoyl)-2,3-dihydro-1H-isoindol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-isoindol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1,3-dihydro-2H-isoindole-2-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(methylsulfonyl)-2,3-dihydro-1H-isoindol-5-yl]pyridin-2(1H)-one;-   1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2-glycoloyl-    1,2,3,4-tetrahydroisoquinolin-6-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(N-methylglycyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxy-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(1H)-one;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridin-2(1H)-one;-   1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2-glycoloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(N-methylglycyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxy-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-methylpyridin-2(1H)-one;-   7-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridin-2(1H)-one;-   1-(1-acetyl-1H-benzimidazol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-1H-benzimidazol-5-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1    (N-methylglycyl)-1H-benzimidazol-5-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-1H-benzimidazol-5-yl]pyridin-2(1H)-one;-   3-chloro-1-(1,3-diacetyl-2,3-dihydro-1H-benzimidazol-5-yl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-(3-acetyl-1-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-acetyl-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-acetyl-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-acetyl-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-acetyl-1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-acetyl-5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-(1-acetyl-3-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,3-diglycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(N-methylglycyl)-2,3-dihydro-1H    benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-glycoloyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1-acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-glycoloyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1,3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(2-hydroxy-2-methylpropanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(2-hydroxy-2-methylpropanoyl)-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(2-hydroxy-2-methylpropanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1-acetyl-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-glycoloyl-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1,3-bis(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(N-methylglycyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridin-2(1H)-one;-   1-[1-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-glycoloyl-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxypropanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1,3-bis(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxypropanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-glycoloyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-methylbutanoyl)-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-methylbutanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-methylbutanoyl)-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   1-[1,3-bis(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-methylbutanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-acetyl-6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-glycoloyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-benzimidazole-1,3(2H)-dicarboxamide;-   6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-[1-acetyl-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-glycoloyl-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-6-methylpyridin-2(1H)-one;-   5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-[1,3-bis(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[3-acetyl-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-(1-acetyl-1H-pyrrol-3-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-1H-pyrrol-3-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-1H-pyrrol-3-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-1H-pyrrol-3-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-1H-pyrrol-3-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-1H-pyrrol-3-yl]-6-methylpyridin-2(1H)-one;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-pyrrole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-1H-pyrrol-3-yl]pyridin-2(1H)-one;-   1-(1-acetyl-1H-imidazol-4-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-1H-imidazol-4-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-1H-imidazol-4-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-1H-imidazol-4-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-1H-imidazol-4-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-1H-imidazol-4-yl]-6-methylpyridin-2(1H)-one;-   4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-imidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-1H-imidazol-4-yl]pyridin-2(1H)-one;-   1-(1-acetyl-1H-pyrazol-4-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-1H-pyrazol-4-yl)-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-methylpropanoyl)-1H-pyrazol-4-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(N-methylglycyl)-1H-pyrazol-4-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxypropanoyl)-1H-pyrazol-4-yl]-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-methylbutanoyl)-1H-pyrazol-4-yl]-6-methylpyridin-2(1H)-one;-   4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-1H-pyrazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[1-(methylsulfonyl)-1H-pyrazol-4-yl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-isoquinolin-7-yl-6-methylpyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(isoquinolin-6-ylmethyl)pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-indol-2-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-1H-indol-5-ylmethyl)pyridin-2(1H)-one;-   1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(N-methylglycyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxypropanoyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}indoline-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-1H-isoindol-5-ylmethyl)pyridin-2(1H)-one;-   1-[(2-acetyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(2-glycoloyl-2,3-dihydro-1H-isoindol-5-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(N-methylglycyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxypropanoyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}pyridin    2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-isoindole-2-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(methylsulfonyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)pyridin-2(1H)-one;-   1-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(2-glycoloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(N-methylglycyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxy-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(1H)-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)pyridin-2(1H)-one;-   1-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(2-glycoloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(2-hydroxy-2-methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(N-methylglycyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxy-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-1H-benzimidazol-5-yl)methyl)pyridin-2(1H)-one;-   1-[(1-acetyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-[(3-acetyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-1-[(1,3-diacetyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   1-[(3-acetyl-1-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   1-{[3-acetyl-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   1-{[3-acetyl-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   1-{[3-acetyl-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   1-{[3-acetyl-1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-{[3-acetyl-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(3-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]pyridin-2(1H)-one;-   1-[(1-acetyl-3-glycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1,3-diglycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-1-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1-acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-glycoloyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1,3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(2-hydroxy-2-methylpropanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(2-hydroxy-2-methylpropanoyl)-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(2-hydroxy-2-methylpropanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1-acetyl-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-glycoloyl-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1,3-bis(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxypropanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(N-methylglycyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-glycoloyl-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxypropanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1,3-bis(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxypropanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-glycoloyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxy-3-methylbutanoyl)-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxy-3-methylbutanoyl)-1-(N-methylglycyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxy-3-methylbutanoyl)-1-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-{([1,3-bis(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(3-hydroxy-3-methylbutanoyl)-1-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-2,3-dihydro-1H-benzimidazole    1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1H-benzimidazole-1,3(2H)-dicarboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   1-{[1-acetyl-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-glycoloyl-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(N-methylglycyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxypropanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-hydroxy-3-methylbutanoyl)-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazol-5-yl]methyl}pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(methylsulfonyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   1-{[1,3-bis(methylsulfonyl)-2,3-dihydro-1H    benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2-oxo-2,3-dihydro-1H    benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one;-   1,3-diacetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-diglycoloyl-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1-(N-methylglycyl)-1,3-dihydro-2H    benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-3-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-bis(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-3-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-3-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-bis(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxypropanoyl)-3-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-3-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-3-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-3-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-bis(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-3-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole    1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-3-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1-(N-methylglycyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1-(3-hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-bis(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-glycoloyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(N-methylglycyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxypropanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-2-oxo-1H-benzimidazole-1,3(2H)-dicarboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(methylsulfonyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-glycoloyl-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(2-hydroxy-2-methylpropanoyl)-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(N-methylglycyl)-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxypropanoyl)-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-3-(methylsulfonyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}-1,3-bis(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;-   3-benzyl-4-hydroxy-1-(2-phenylethyl)pyridin-2(1H)-one;-   1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   1-benzyl-4-chloro-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   methyl    5-chloro-1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carboxylate;-   5-bromo-1-(2-chloro-6-fluorobenzyl)-3-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorophenyl)ethynyl]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorophenyl)ethynyl]-6-methylpyridin-2(1H)-one;-   methyl    3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate;-   4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile;-   4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one;-   3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzaldehyde;-   4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoic    acid;-   4-[(2,4-difluorobenzyl)oxy]-1-[4-(dimethylamino)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one;-   methyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate;-   3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic    acid;-   4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one;-   3-bromo-1-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(hydroxymethyl)-2-methoxyphenyl]-6-methylpyridin-2(1H)-one;-   methyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}pyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-[2-(dimethylamino)ethyl]benzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)benzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-N-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)-N-methylbenzamide;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   methyl    3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate;-   4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-methylbenzoic    acid;-   1-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-[(1-acetyl-1H-indol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one;-   methyl    2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-3,5-difluorobenzylcarbamate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{4-[(4-methylpiperazin-1-yl)carbonyl]benzyl}pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indol-5-ylmethyl)pyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)-4-methylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N,4-trimethylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-methyl-5-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;-   1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(4-methoxybenzyl)-4-phenoxypyridin-2(1H)-one;-   1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-dimethylaminomethyl-benzyl)-6-methyl-1H-pyridin-2-one;-   N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-2-hydroxy-acetamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl    1-[4-(piperidine-1-carbonyl)-benzyl]-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(ethoxyamino)methyl]pyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-isopropyl-benzamide;-   N-(3-aminopropyl)-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide    hydrochloride;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N,N-bis-(2-hydroxy-ethyl)-benzamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[4-(pyrrolidine-1-carbonyl)-benzyl]-1H-pyridin-2-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-hydroxy-benzamide;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-methyl-benzamide;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-dimethylamino-ethyl)-benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-ylmethyl)pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[4-(4-methyl-piperazine-1-carbonyl)-benzyl]-1H-pyridin-2-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzaldehyde;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-dimethylaminomethyl-benzyl)-6-methyl-1H-pyridin-2-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)-4-methylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(1H)-one    hydrochloride;-   N-(2-aminoethyl)-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide    hydrochloride;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-hydroxy-ethyl)-benzamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-hydroxymethyl-benzyl)-6-methyl-1H-pyridin-2-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-methoxy-ethyl)-benzamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-{4-[(2-hydroxy-ethylamino)-methyl]-benzyl}-6-methyl-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-methyl-5-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(4-methylaminomethyl-benzyl)-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[4-(morpholine-4-carbonyl)-benzyl]-1H-pyridin-2-one;-   N-(2-aminoethyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   N-(3-aminopropyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide    hydrochloride;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-methoxy-ethyl)-N-methyl-benzamide;-   1-(4-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[4-(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H)-one    hydrochloride;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[4-(isopropylamino-methyl)-benzyl]-6-methyl-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-{3-[(2-hydroxy-ethylamino)-methyl]-benzyl}-6-methyl-1H-pyridin-2-one;-   1-(3-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-hydroxy-benzyl)-6-methyl-1H-pyridin-2-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(1H)-one;-   N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-acetamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one;-   ethyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate;-   1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one    trifluoroacetate;-   1-(3-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[3-(isopropylamino-methyl)-benzyl]-6-methyl-1H-pyridin-2-one;-   {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-carbamic    acid tert-butyl ester;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-6-methyl-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-dimethylaminomethyl-benzyl)-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(3-piperidin-1-ylmethyl-benzyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-{[(2-methoxyethyl)amino]methyl}pyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-methylbenzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,4-difluoro-6-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(3-morpholin-4-ylmethyl-benzyl)-1H-pyridin-2-one;-   3-bromo-1-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one;-   1-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one;-   4-Benzyloxy-3-bromo-1-(4-fluoro-benzyl)-1H-pyridin-2-one;-   4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N,4-trimethylbenzamide;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-isopropylbenzamide;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzamide;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzonitrile;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(3-piperazin-1-ylmethyl-benzyl)-1H-pyridin-2-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-hydroxy-ethyl)-N-methyl    benzamide;-   methyl    4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[3-(morpholine-4-carbonyl)benzyl]-1H-pyridin-2-one;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N,N-bis(2-hydroxy-ethyl)-benzamide;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzoic    acid methyl ester;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-hydroxy-benzamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-hydroxymethyl-benzyl)-6-methyl-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-fluoro-benzyl)-1H-pyridin-2-one;-   N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-methanesulfonamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[3-(pyrrolidine-1-carbonyl)-benzyl]-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   N-(3-aminopropyl)-3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide    hydrochloride;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-methylaminomethyl-benzyl)-1H-pyridin-2-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-dichlorobenzenesulfonamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(dimethylamino)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(4-piperidin-1-ylmethyl-benzyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   N-(2-aminoethyl)-3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide    hydrochloride;-   3-bromo-1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-chloro-1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide;-   2-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}-acetamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H)-one    hydrochloride;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzoic    acid methyl ester;-   1-(3-Aminomethyl-2-fluoro-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(morpholin-4-ylmethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indol-5-ylmethyl)pyridin-2(1H)-one;-   1-[3-(aminomethyl)benzyl]-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one    trifluoroacetate;-   1-[3-(2-aminoethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one    trifluoroacetate;-   1-[3-(aminomethyl)benzyl]-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-methoxy-benzyl)-6-methyl-1H-pyridin-2-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N,N-dimethyl-benzamide;-   3-bromo-6-methyl-1-(pyridin-4-ylmethyl)-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzamide;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-methyl-benzamide;-   {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-carbamic    acid methyl ester;-   3-bromo-4-[(2,6-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzonitrile;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;-   1-Benzyl-4-benzyloxy-3-bromo-6-methyl-1H-pyridin-2-one;-   1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one;-   1-Benzyl-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}-acetonitrile;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-(2-hydroxy-ethyl)-benzamide;-   3-Chloro-4-(2,4-difluoro-benzyloxy)-1-(3-fluoro-benzyl)-1H-pyridin-2-one;-   1-Allyl-3-chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin 2    one;-   3-Chloro-4-(2,4-difluoro-benzyloxy)-1-[4-(isopropylamino-methyl)-benzyl]-1H-pyridin-2-one;-   methyl    3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(4-piperazin-1-ylmethyl-benzyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N,N-dimethyl-benzamide;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(1H)-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(3-methyl-benzyloxy)-1H-pyridin-2-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(isoquinolin-5-ylmethyl)pyridin-2(1H)-one    trifluoroacetate;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   1-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzamide;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzoic    acid;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(4-morpholin-4-ylmethyl-benzyl)-1H-pyridin-2-one;-   4-(2,4-Difluoro-benzyloxy)-1-(3-fluoro-benzyl)-3-iodo-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-hydroxybenzamide;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(2,6-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzonitrile;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(pyrrolidin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one;-   3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-N-isopropyl-benzamide;-   3-bromo-1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-chlorobenzyl)pyridin-2(1H)-one;-   4-Benzyloxy-3-bromo-1-(4-chloro-benzyl)-1H-pyridin-2-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-1-(4-fluoro-benzyl)-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one;-   methyl    4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzoic acid;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoic acid;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one;-   N-(2-aminoethyl)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide    hydrochloride;-   4-Benzyloxy-3-bromo-1-(4-methylsulfanyl-benzyl)-1H-pyridin-2-one;-   1-Benzyl-4-benzyloxy-3-chloro-1H-pyridin-2-one;-   4-(benzyloxy)-3-bromo-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-chloropyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[3-(isopropylamino-methyl)-benzyl]-1H-pyridin-2-one;-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluoro-benzamide;-   5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2,3-dihydroxypropyl)pyrazine-2-carboxamide;-   {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}-acetic    acid ethyl ester;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-N-hydroxy-benzamidine;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide;-   ethyl    5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-methoxy-benzyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-methoxybenzyl)pyridin-2(1H)-one;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzoic acid    methyl ester;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-dimethylaminomethyl-benzyl)-1H-pyridin-2-one;-   3-Chloro-4-(2,4-difluoro-benzyloxy)-1-(3-methanesulfonyl-benzyl)-1H-pyridin-2-one;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzoic acid    methyl ester;-   methyl    4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   ethyl    5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate;-   4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzonitrile;-   {3-[3-Bromo-4-(4-fluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-carbamic    acid tert-butylester;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one;-   1-(3-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-1H-pyridin-2-one;    ylmethyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-bromobenzyl)pyridin-2(1H)-one;-   4-Benzyloxy-3-bromo-1-(4-bromo-benzyl)-1H-pyridin-2-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(piperazin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one    hydrochloride;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   3-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzoic acid    methyl ester;-   3-bromo-1-(3-fluorobenzyl)-4-{([2-(hydroxymethyl)benzyl]oxy}pyridin-2(1H)-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(2-hydroxymethyl-benzyloxy)-1H-pyridin-2-one;-   1-Benzo-[1,3]dioxol-5-ylmethyl-3-bromo-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one;-   3-bromo-4-[(2,6-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-Bromo-4-(3-chloro benzyloxy)-1-(3-fluoro-benzyl)-1H-pyridin-2-one;-   4-(benzyloxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-Benzyloxy-3-bromo-1-(3-fluoro-benzyl)-1H-pyridin-2-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-[3-(piperidine-1-carbonyl)-benzyl]-1H-pyridin-2-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N-dimethylbenzamide;-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluoro-benzoic    acid methyl ester;-   1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one;-   1-(3-Fluoro-benzyl)-4-(4-fluoro-benzyloxy)-3-iodo-1H-pyridin-2-one;-   N-(3-aminopropyl)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide    hydrochloride;-   4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   4-[3-Bromo-4-(4-fluoro-benzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzonitrile;-   3-Bromo-1-(3-fluoro-benzyl)-4-(2,3,4-trifluoro-benzyloxy)-1H-pyridin-2-one;-   1-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide;-   4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl)-benzonitrile;-   3-bromo-1-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-Bromo-1-(2,4-difluoro-benzyl)-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)benzamide;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   1-Benzyl-4-benzyloxy-3-bromo-1H-pyridin-2-one;-   3-bromo-1-(cyclopropylmethyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-(4-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-1H-pyridin-2-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one;-   3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzoic    acid methyl ester;-   5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylpyrazine-2-carboxamide;-   3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H)-one;-   3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-one    hydrochloride;-   1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl    methyl(phenyl)carbamate;-   4-(benzylamino)-1-(3-fluorobenzyl)-6-methyl-3-nitropyridin-2(1H)-one;-   tert-butyl    4-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]piperazine-1-carboxylate;-   ethyl[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]acetate;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]benzenesulfonamide;-   3-bromo-4-[(4-tert-butylbenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-1-phenylmethanesulfonamide;-   1-(biphenyl-2-ylmethyl)-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-(biphenyl-2-ylmethoxy)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorophenyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-anilino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   methyl    4-{[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]amino}benzoate;-   3-bromo-1-(3-fluorobenzyl)-4-[(3,4,5-trimethoxyphenyl)amino]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[4-(4-fluorophenyl)piperazin-1-yl]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-(4-methylpiperazin-1-yl)pyridin-2(1H)-one    trifluoroacetate;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-2,5-difluorobenzamide;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-2,4-difluorobenzamide;-   3-bromo-1-(cyclohexylmethyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanoic acid;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-N′-(2,4-difluorophenyl)urea;-   3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanamide;-   4-(benzyloxy)-3-bromo-1-(3-morpholin-4-yl-3-oxopropyl)pyridin-2(1H)-one;-   N-(3-aminopropyl)-3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanamide    hydrochloride;-   4-(benzyloxy)-3-bromo-1-(3-oxo-3-piperazin-1-ylpropyl)pyridin-2(1H)-one    hydrochloride;-   4-(benzyloxy)-3-bromo-1-(2-morpholin-4-ylethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-{[4-fluoro-2-(trifluoromethyl)benzyl]amino}pyridin-2(1H)-one;-   N-(2-aminoethyl)-3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanamide    hydrochloride;-   [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]acetic    acid;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(tetrahydrofuran-2-ylmethyl)pyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(tetrahydrofuran-2-ylmethyl)pyridin-2(1H)-one;-   methyl    3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridine-1(2H)-carboxylate;-   1-allyl-3-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(2,2-diethoxyethyl)pyridin-2(1H)-one;-   methyl N-acetyl-3-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]alaninate;-   benzyl N-acetyl-3-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]alaninate;-   benzyl    N-[(benzyloxy)carbonyl]-3-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]alaninate;-   4-(benzyloxy)-1-(2-oxopropyl)pyridin-2(1H)-one;-   5-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}-5-methylimidazolidine-2,4-dione;-   ethyl[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]acetate;-   2-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]acetamide;-   1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H)-one;-   4-(benzyloxy)-1-ethylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;-   4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   tert-butyl    3-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}piperidine-1-carboxylate;-   1,3-dibenzyl-4-hydroxy-6-methylpyridin-2(1H)-one;-   1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;-   4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   1-benzyl-4-(1-naphthylmethoxy)pyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)-3,5-dibromopyridin-2(1H)-one;-   1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-3-[(benzylamino)methyl]-4-(benzyloxy)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-{[(2-cyclohexylethyl)amino]methyl}pyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)-5-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    methanesulfonate;-   1-benzyl-3-bromo-6-methyl-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;-   1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    4-bromobenzenesulfonate;-   1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl    4-bromobenzenesulfonate;-   4-phenoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-2(1H)-one;-   1-benzyl-4-phenoxypyridin-2(1H)-one;-   1-(4-methoxybenzyl)-4-phenoxypyridin-2(1H)-one;-   3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one    hydrochloride;-   4-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-one;-   1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(E)-2-(4-fluorophenyl)vinyl]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)pyridin-2(1H)-one;-   1-benzyl-4-(benzylthio)pyridin-2(1H)-one;-   methyl    4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]benzoate;-   benzyl (5-nitro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate;-   ethyl    3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-1,2′-bipyridine-5′-carboxylate;-   4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one;-   [5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]methyl    carbamate;-   4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one;-   methyl    (2E)-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]but-2-enoate;-   4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H)-one;-   tert-butyl    4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}piperidine-1-carboxylate;-   4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-dihydroxyethyl)-6-methylpyridin-2(1H)-one;-   1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one;-   4-({[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)benzonitrile;-   1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde    oxime;-   1-benzyl-4-(benzylthio)-3-methylpyridin-2(1H)-one;-   1-benzyl-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-(1-phenylethoxy)pyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   2-({[3-bromo-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-(trifluoromethyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-oxiran-2-ylpyridin-2(1H)-one;-   1-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde;-   tert-butyl    3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}piperidine-1-carboxylate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-[2-(phenylthio)ethyl]pyridin-2(1H)-one;-   3-Bromo-4-(4-chloro-benzyloxy)-1-(2-phenylsulfanyl-ethyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-morpholin-4-ylethyl)pyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;-   4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   4-Benzyloxy-3-bromo-1-methanesulfonyl-1H-pyridin-2-one;-   tert-butyl    4-[4-benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]piperidine-1-carboxylate;-   1 benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(2-methyl-4-methylamino-pyrimidin-5-ylmethyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(methylsulfonyl)benzyl]pyridin-2(1H)-one;-   4-Phenoxy-1H-pyridin-2-one;-   1-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   methyl 4-{[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one    hydrochloride;-   4-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one    hydrochloride;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(methylthio)pyrimidin-4-yl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-piperidin-4-ylpyridin-2(1H)-one    hydrochloride;-   4-Benzyloxy-1-difluoromethyl-1H-pyridin-2-one;-   4-Benzyloxy-3-bromo-1-(2-chloro-phenyl)-6-methyl-1H-pyridin-2-one;-   3-Bromo-6-methyl-1-pyridin-3-ylmethyl-4-[(pyridin-3-ylmethyl)-amino]-1H-pyridin-2-one;-   1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (2,4-difluoro-phenyl)-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (2,4-difluoro-phenyl)-amide;-   5-Chloro-1-(2,6-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid (2,4-difluoro-phenyl)-amide;-   5-Chloro-1-(2,6-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid methyl-phenyl-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    benzylamide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (3-dimethylamino-propyl)-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (2-morpholin-4-yl-ethyl)-amide;-   N-[5-Acetyl-1-(4-chloro-benzyl)-6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl]-4-chloro-benzamide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    N′-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-hydrazide;-   N-allyl-2-[(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)carbonyl]hydrazinecarbothioamide;-   1-Benzyl-5-[5-(3,4-dichloro-benzylsulfanyl)-[1,3,4]oxadiazol-2-yl]-1H-pyridin-2-one;-   N′-{[(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)carbonyl]oxy}pyridine-4-carboximidamide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    3-trifluoromethyl-benzylamide;-   1-Benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (2-morpholin-4-yl-ethyl)-amide;-   5-[4-(3-Chloro-phenyl)-piperazine-1-carbonyl]-1-(3,4-dichloro-benzyl)-1H-pyridin-2-one;-   5-Chloro-1-(2,6-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid benzylamide;-   1-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1H-pyridin-2-one;-   1-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1H-pyridin-2-one;-   2-Chloro-N-[1-(2,6-dichloro-benzyl)-6-oxo-5-trifluoromethyl-1,6-dihydro-pyridin-3-yl]-4-fluoro-benzamide;-   N-[1-(2,6-Dichloro-benzyl)-6-oxo-5-trifluoromethyl-1,6-dihydro-pyridin-3-yl]-4-isopropoxy-benzamide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (4-trifluoromethoxy-phenyl)-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (3-trifluoromethyl-phenyl)-amide;-   5-Chloro-1-(2,6-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid (3-trifluoromethyl-phenyl)-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (4-chloro-phenyl)-amide;-   1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid    (2-dimethylamino-ethyl)-amide;-   5-Methyl-1-phenyl-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(3-methoxy-phenyl)-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(3-isopropyl-phenyl)-1H-pyridin-2-one;-   3′-Bromo-1′-(3-fluoro-benzyl)-6-methoxy-1′H-[3,4′]bipyridinyl-2′-one;-   4-Benzo[1,3]dioxol-5-yl-3-bromo-1-(3-fluoro-benzyl)-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-thiophen-3-yl-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(3-trifluoromethyl-phenyl)-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-naphthalen-2-yl-1H-pyridin-2-one;-   3-Bromo-1-(3-fluoro-benzyl)-4-(4-fluoro-phenyl)-1H-pyridin-2-one;-   1-Benzenesulfonyl-4-benzyloxy-3-bromo-1H-pyridin-2-one;-   4-[3-Amino-1-(2,4-difluoro-phenyl)-propoxy]-3-bromo-6-methyl-1-pyridin-3-ylmethyl-1H-pyridin-2-one;-   1-(4-Bromo-2,6-difluoro-phenyl)-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   2-[1-(4-Amino-2-methyl-pyrimidin-5-ylmethyl)-3-bromo-6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxymethyl]-5-fluoro-benzonitrile;-   4-(2,4-Difluoro-benzyloxy)-6-methyl-1-(2,4,6-trifluoro-phenyl)-1H-pyridin-2-one;-   1-(2-Chloro-4-hydroxy-phenyl)-4-(2,4-difluoro-benzyloxy)-6-methyl-1H-pyridin-2-one;-   3-[4-(2,4-Difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-benzoic    acid methyl ester;-   3-Bromo-1-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-vinyl-1H-pyridin-2-one;-   3-Bromo-1-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-styryl-1H-pyridin-2-one;-   1-(2,6-Difluoro-phenyl)-4-methoxy-6-methyl-5-phenethyl-1H-pyridin-2-one;-   3-Bromo-1-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-phenethyl-1H-pyridin-2-one;-   1-(1H-indazol-5-yl)-4-(1H-indazol-5-ylamino)-6-methylpyridin-2(1H)-one;-   5-Bromo-4-(2,4-difluoro-benzyloxy)-1-(2,6-difluoro-phenyl)-2-[2-(2,4-difluoro-phenyl)-ethyl]-6-oxo-1,6-dihydro-pyridine-3-carbaldehyde;-   4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-pyrimidine-2-carbonitrile;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[1,2′]bipyridinyl-5′-carboxylic    acid;-   3-Bromo-4-(5-carboxy-pyridin-2-yloxy)-6-methyl-2-oxo-2H-[1,2′]bipyridinyl-5′-carboxylic    acid;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6,6′-dimethyl-2-oxo-2H-[1,2′]bipyridinyl-3′-carbonitrile;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[1,2′]bipyridinyl-5′-carboxylic    acid methylamide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[1,2′]bipyridinyl-5′-carboxylic    acid (2-hydroxy-ethyl)-amide;-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[1,2′]bipyridinyl-5′-carboxylic    acid (2-methoxy-ethyl)-amide;-   3-Bromo-1-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-(4-methyl-benzyl)-1H-pyridin-2-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-dihydroxy-2-phenylethyl)-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-5′-(1-hydroxy-1-methylethyl)-6-methyl-2H-1,2′-bipyridin-2-one;-   4-Benzyloxy-1H-pyridin-2-one;-   4-Benzyloxy-3-methyl-1H-pyridin-2-one;-   2-Oxo-6-phenethyl-1,2-dihydro-pyridine-3-carbonitrile;-   2-Oxo-6-phenyl-1,2-dihydro-pyridine-3-carbonitrile;-   6-Oxo-1,6-dihydro-[2,3′]bipyridinyl-5-carbonitrile;-   6-Oxo-1,6-dihydro-[2,3′]bipyridinyl-5-carboxylic acid;-   3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   3-chloro-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-chloro-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-4-[(3,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic    acid;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(1-hydroxy-1-methylethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;-   4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-6-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one    trifluoroacetate;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-methylbenzamide;-   1-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   1-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[3-(piperidin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-2(1H)-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-hydroxybenzamide;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   3-bromo-1-(cyclopropylmethyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(cyclopropylmethyl)-4-[(4    fluorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one    trifluoroacetate;-   3-bromo-1-(3-fluorobenzyl)-4-[(2-methylbenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(2-methylbenzyl)oxy]pyridin-2(1H)-one;-   methyl    3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one;-   3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic    acid;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-[2-(hydroxymethyl)benzyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(5-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrazin-2-yl)methyl]-6-methylpyridin-2(1H)-one    trifluoroacetate(salt);-   4-(benzyloxy)-3-bromo-1-[(6-fluoropyridin-3-yl)methyl]pyridin-2(1H)-one;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-chloro-2-fluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one;-   2-(2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}phenyl)acetamide;-   1-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   1-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;-   methyl    2-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]methyl}benzoate;-   3-bromo-1-(2,6-dichlorophenyl)-4-[2-(4-fluorophenyl)ethyl]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(2,6-dichlorophenyl)-4-[2-(4-fluorophenyl)ethyl]-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(isopropylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-one    hydrochloride;-   3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-N′-methylurea;-   3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(2-thienyl)ethyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(2-thienyl)ethyl]pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-methoxybenzyl)pyridin-2(1H)-one;-   3-bromo-1-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(4-methoxybenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one;-   N′-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-N,N-dimethylurea;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}morpholine-4-carboxamide;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}methanesulfonamide;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-isopropylbenzamide;-   4-(allylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   4-(allylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   (4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}phenyl)acetic    acid;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one;-   1-(biphenyl-4-ylmethyl)-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoic    acid;-   4-(benzyloxy)-3-bromo-1-[2-(3-thienyl)ethyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-[2-(3-thienyl)ethyl]pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-4-fluorobenzamide;-   methyl    3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate;-   1-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-(4-tert-butylbenzyl)pyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-2-methoxyacetamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(dimethylamino)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[4-(piperazin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one    hydrochloride;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N-bis(2-hydroxyethyl)benzamide;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-one    hydrochloride;-   1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one;-   1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-methylpyridin-2(1H)-one;-   4-(benzyloxy)-1-(piperidin-3-ylmethyl)pyridin-2(1H)-one    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one;-   N¹-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}glycinamide    hydrochloride;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[4-(piperidin-1-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-2,6-difluorobenzamide;-   2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile;-   5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-methylpyrazine-2-carboxamide;-   3-chloro-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoic    acid;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-fluorobenzyl)amino]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-[(3-methoxybenzyl)oxy]pyridin-2(1H)-one;-   3-bromo-1-(4-tert-butylbenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}acetamide;-   2-{[3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}amino)-2-oxoethyl    acetate;-   1-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}urea;-   1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one;-   N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-2-hydroxyacetamide;-   3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-2(1H)-one;-   3-bromo-1-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one;-   1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;-   2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide;-   1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   1-[2-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one;-   methyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanoate;-   1-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H)-one;-   4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(1H)-one;-   4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N-dimethylbenzamide;-   {4-[({4-(benzyloxy)-3-bromo-1-[4-(carboxymethyl)benzyl]-1,2-dihydropyridin-2-yl}oxy)methyl]phenyl}acetic    acid;-   4-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one;-   4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{3-[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one;-   1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-{[4-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;-   4-(benzylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one;-   4-[(2,4-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one;-   4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide;-   4-(benzyloxy)-3-bromo-1-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one;-   5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxylic    acid;-   1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;-   3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoic    acid;-   4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzoic acid;-   ethyl    N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)glycinate    trifluoroacetate;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-[(E)-2-phenylvinyl]pyridin-2(1H)-one;-   3-bromo-1-(3-fluorobenzyl)-4-{[3-(trifluoromethyl)benzyl]amino}pyridin-2(1H)-one;-   3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-phenylpropyl)pyridin-2(1H)-one;-   3-bromo-1-(4-tert-butylbenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one;-   4-(allylamino)-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one;-   1-cyclohexyl-4-[(2,4-difluorobenzyl)oxy]-3,6-dimethylpyridin-2(1H)-one;-   3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(1H)-one;-   1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydropyridine-3-carbaldehyde;-   4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-yn-1-ylpyridin-2(1H)-one;-   ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanoate;-   1-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(1H)-one;

or a pharmaceutically acceptable salt thereof.

-   3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(5-methyl-pyrazin-2-ylmethyl)-1H-pyridin-2-one-   3-Chloro-4-(2,4-difluoro-benzyloxy)-1-(5-hydroxymethyl-pyrazin-2-ylmethyl)-6-methyl-1H-pyridin-2-one-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-one-   3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[1-(2-hydroxy-acetyl)-2,3-dihydro-1H-indol-5-ylmethyl]-6-methyl-1H-pyridin-2-one-   3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-1-(1H-pyrazol-3-ylmethyl)-1H-pyridin-2-one-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4,N-dimethyl-benzamide-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4-methyl-benzamide-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4-fluoro-N-methyl-benzamide-   4-Chloro-3-[3-chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-N-methyl-benzamide-   3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-4-fluoro-benzamide-   4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-yl]-3,N-dimethyl-benzamide-   3-Chloro-4-(2,4-difluoro-benzyloxy)-1-[4-(1,2-dihydroxy-ethyl)-2-methyl-phenyl]-6-methyl-1H-pyridin-2-one-   N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}-2-hydroxy-acetamide-   1-Hydroxy-cyclopropanecarboxylic acid    4-[3-chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzylamide-   N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-benzyl}-2-hydroxy-acetamide-   N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}acetamide-   {2-[3-Bromo-1-(2,6-difluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxymethyl]-5-fluoro-benzyl}-carbamic    acid ethyl ester

The above names were generated using ChemDraw Ultra version 6.0.2, whichis put out by CambridgeSoft.com, Cambridge, Mass.; or ACD Nameproversion 5.09, which is put out by ACDlabs.com.

DEFINITIONS

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon of a designed number of carbon atoms containing at least onecarbon-carbon double bond. Examples of “alkenyl” include vinyl, allyl,and 2-methyl-3-heptene.

The term “alkoxy” represents an alkyl attached to the parent molecularmoiety through an oxygen bridge. Examples of alkoxy groups include, forexample, methoxy, ethoxy, propoxy and isopropoxy.

The term “thioalkoxy” represents an alkyl attached to the parentmolecular moiety through a sulfur atom. Examples of thioalkoxy groupsinclude, for example, thiomethoxy, thioethoxy, thiopropoxy andthioisopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. “Cx-Cy alkyl” represents an alkyl group of the specifiednumber of carbons. For example, C₁-C₄ alkyl includes all alkyl groupsthat include at least one and no more than four carbon atoms. It alsocontains subgroups, such as, for example, C₂-C₃ alkyl or C₁-C₃ alkyl.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl.Preferred examples of aryl groups include phenyl and naphthyl. The mostpreferred aryl group is phenyl. The aryl groups herein are unsubstitutedor, as specified, substituted in one or more substitutable positionswith various groups. Thus, such aryl groups can be optionallysubstituted with groups such as, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono- or di-(C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “arylalkyl” refers to an aryl group, as defined above, attachedto the parent molecular moiety through an alkyl group, as defined above.Preferred arylalkyl groups include, benzyl, phenethyl, phenpropyl, andphenbutyl. More preferred arylalkyl groups include benzyl and phenethyl.The most preferred arylalkyl group is benzyl. The aryl portions of thesegroups are unsubstituted or, as specified, substituted in one or moresubstitutable positions with various groups. Thus, such aryl groups canbe optionally substituted with groups such as, for example, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “arylalkoxy” refers to an aryl group, as defined above,attached to the parent molecular moiety through an alkoxy group, asdefined above. Preferred arylaloxy groups include, benzyloxy,phenethyloxy, phenpropyloxy, and phenbutyloxy. The most preferredarylalkoxy group is benzyloxy.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. More preferred cycloalkyl groups includecyclopropyl.

The term “cycloalkylalkyl,” as used herein, refers to a C₃-C₈ cycloalkylgroup attached to the parent molecular moiety through an alkyl group, asdefined above. Examples of cycloalkylalkyl groups includecyclopropylmethyl and cyclopentylethyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, oriodine.

The term “heterocycloalkyl,” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein the non-aromatic heterocycle is attached to the core.The heterocycloalkyl ring may be optionally fused to or otherwiseattached to other heterocycloalkyl rings, aromatic heterocycles,aromatic hydrocarbons and/or non-aromatic hydrocarbon rings. Preferredheterocycloalkyl groups have from 3 to 7 members Examples ofheterocycloalkyl groups include, for example, piperazine,1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine, tetrahydrofuran,pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups includepiperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl. Theheterocycloalkyl groups herein are unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.Thus, such heterocycloalkyl groups can be optionally substituted withgroups such as, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono- or di-(C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. Preferredheteroaryl groups include pyridyl. The heteroaryl groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. Thus, such heteroaryl groups can beoptionally substituted with groups such as, for example, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono ordi-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroarylalkyl” refers to a heteroaryl group, as definedabove, attached to the parent molecular moiety through an alkyl group,as defined above. Preferred heteroarylalkyl groups include,pyrazolemethyl, pyrazoleethyl, pyridylmethyl, pyridylethyl,thiazolemethyl, thiazoleethyl, imidazolemethyl, imidazoleethyl,thienylmethyl, thienylethyl, furanylmethyl, furanylethyl,isoxazolemethyl, isoxazoleethyl, pyrazinemethyl and pyrazineethyl. Morepreferred heteroarylalkyl groups include pyridylmethyl and pyridylethyl.The heteroaryl portions of these groups are unsubstituted or, asspecified, substituted in one or more substitutable positions withvarious groups. Thus, such heteroaryl groups can be optionallysubstituted with groups such as, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono- or di-(C₁-C₆)alkylamino,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

If two or more of the same substituents are on a common atom, e.g.,di(C₁-C₆)alkylamino, it is understood that the nature of each group isindependent of the other.

As used herein, the term “p38 mediated disorder” refers to any and alldisorders and disease states in which p38 plays a role, either bycontrol of p38 itself, or by p38 causing another factor to be released,such as but not limited to IL-1, IL-6 or IL-8. A disease state in which,for instance, IL-1 is a major component, and whose production or action,is exacerbated or secreted in response to p38, would therefore beconsidered a disorder mediated by p38.

As TNF-beta has close structural homology with TNF-alpha (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, the synthesis of both TNF-alpha andTNF-beta are inhibited by the compounds of the present invention andthus are herein referred to collectively as “TNF” unless specificallydelineated otherwise.

Non-toxic pharmaceutically acceptable salts include, but are not limitedto salts of inorganic acids such as hydrochloric, sulfuric, phosphoric,diphosphoric, hydrobromic, and nitric or salts of organic acids such asformic, citric, malic, maleic, fumaric, tartaric, succinic, acetic,lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,salicylic and stearic. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography or selective crystallization, andremoving the resolving agent to generate the original compound inenantiomerically enriched form. Any of the above procedures can berepeated to increase the enantiomeric purity of a compound.

The compounds of the invention may exist as atropisomers, i.e., chiralrotational isomers. The invention encompasses the racemic and theresolved atropisomers. The following illustration generically shows acompound (Z) that can exist as atropisomers as well as its two possibleatropisomers (A) and (B). This illustration also shows each ofatropisomers (A) and (B) in a Fischer projection. In this illustration,R₁, R₂, and R₄ carry the same definitions as set forth for Formula I,R_(p′), is a substituent within the definition of R₅, and R_(p) is anon-hydrogen substituent within the definition of R₅.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension, or liquid. The pharmaceuticalcomposition is preferably made in the form of a dosage unit containing aparticular amount of the active ingredient. Examples of such dosageunits are tablets or capsules.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate, or kaolin,or as soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents and flavoring agents maybe added to provide palatable oral preparations. These compositions maybe preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring, and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative, and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives, andbuffering agents can be dissolved in the vehicle.

The active ingredient may also be administered by injection (IV, IM,subcutaneous or jet) as a composition wherein, for example, saline,dextrose, or water may be used as a suitable carrier. The pH of thecomposition may be adjusted, if necessary, with suitable acid, base, orbuffer. Suitable bulking, dispersing, wetting or suspending agents,including mannitol and PEG 400, may also be included in the composition.A suitable parenteral composition can also include a compound formulatedas a sterile solid substance, including lyophilized powder, in injectionvials. Aqueous solution can be added to dissolve the compound prior toinjection.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound, which enhances absorption or penetrationof the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulfoxideand related analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily, dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The anti-inflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

The amount of therapeutically active compounds that are administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the inflammation or inflammation related disorder, the routeand frequency of administration, and the particular compound employed,and thus may vary widely. The pharmaceutical compositions may containactive ingredients in the range of about 0.1 to 1000 mg, preferably inthe range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100mg/kg body weight, preferably between about 0.1 and about 50 mg/kg bodyweight and most preferably between about 0.5 to 30 mg/kg body weight,may be appropriate. The daily dose can be administered in one to fourdoses per day. In the case of skin conditions, it may be preferable toapply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available compounds, orprepared using well-known synthetic methods.

The compound names in this application were created using ACD Name Proversion 5.09, or ChemDraw ultra version 6.0.2, software.

General Synthetic Procedures

Representative procedures for the preparation of compounds of theinvention are outlined below in the Schemes The starting materials canbe purchased or prepared using methods known to those skilled in theart. Similarly, the preparation of the various intermediates can beachieved using methods known in the art. The starting materials may bevaried and additional steps employed to produce compounds encompassed bythe invention, as demonstrated by the examples below. In addition,different solvents and reagents can typically be used to achieve theabove transformations. Protection of reactive groups may also benecessary to achieve the above transformations. In general, the need forprotecting groups, as well as the conditions necessary to attach andremove such groups, will be apparent to those skilled in the art oforganic synthesis. When a protecting group is employed, deprotectionwill generally be required. Suitable protecting groups and methodologyfor protection and deprotection such as those described in ProtectingGroups in Organic Synthesis by Greene and Wuts are known and appreciatedin the art.

In this scheme, R₅ is as defined above.

Alternatively, the compounds of the instant invention can be preparedaccording to the method outlined in Scheme 2.

In Scheme 2, Q at each occurrence is independently alkyl, halogen,alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl,CO₂H, CN, amidinooxime, NR₆R₇, NR₆R₇alkyl, —C(O)NR₆R₇, amidino,haloalkyl, or haloalkoxy; and n is 0, 1, 2, 3, 4, or 5.

Alternatively, compounds of the invention can be prepared using theprocedures outlined in Schemes 3-25. In Schemes 3-25, the X, X′, R, R′,and R″ substituents on groups such as aryl, heteroaryl, amine, andalkyl, carry the same definition described above for substituents onthese groups.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them. Those having skill in the artwill recognize that the starting materials may be varied and additionalsteps employed to produce compounds encompassed by the invention, asdemonstrated by the following examples. Those skilled in the art willalso recognize that it may be necessary to utilize different solvents orreagents to achieve some of the above transformations. In some cases,protection of reactive functionalities may be necessary to achieve theabove transformations. In general, such need for protecting groups, aswell as the conditions necessary to attach and remove such groups, willbe apparent to those skilled in the art of organic synthesis. When aprotecting group is employed, adeprotection step may be required.Suitable protecting groups and methodology for protection anddeprotection such as those described in Protecting Groups in OrganicSynthesis by Greene and Wuts are well known and appreciated in the art.

Unless otherwise specified, all reagents and solvents are of standardcommercial grade and are used without further purification. Theappropriate atmosphere to run the reaction under, for example, air,nitrogen, hydrogen, argon and the like, will be apparent to thoseskilled in the art.

EXAMPLES Example 1 4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H)-one

4-Benzyloxy-2(1H)-pyridone (3.0 g, 0.015 mol), 4-methylbenzyl bromide(3.15 g, 0.17 mol), and potassium carbonate (3.0 g, 0.022 mol) wereheated at 80° C. for 2 hours. Contents were allowed to cool, dilutedwith water and a solid (5.52 g) was filtered. FABHRMS m/z 306.1494 (M+H,C₂₀H₂₀NO₂ requires 306.1494). ¹H NMR (CDCl₃/300 MHz): 7.50-7.40 (m, 5H);7.20-7.05 (m, 5H); 6.07-6.00 (m, 1H); 5.95-5.90 (m, 1H); 5.05 (s, 2H);5.00 (s, 2H); 2.32 (s, 3H).

Anal. Calcd for C₂₀H₁₉NO₂: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.54;H, 6.38; N, 4.58.

Example 2 4-(benzyloxy)-3-bromo-1-(4-methylbenzyl)pyridin-2(1H)-one

The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate(738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15° C.Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was addeddropwise. Contents were stirred 2 hours, coming to room temperature.Water (200 mL) was added and a light yellow solid was filtered. Mp150.4-151.2° C. FABHRMS m/z 384.0599 (M+H, C₂₀H₁₉BrNO₂ requires384.0601). ¹H NMR (CDCl₃/300 MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m,5H); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H).

Anal. Calcd for C₂₀H₁₈BrNO₂: C, 62.51; H, 4.72; N, 3.65. Found: C,62.11; H, 4.48; N, 3.54.

Examples 3-10

The compounds of Examples 3-10 are prepared essentially according to theprocedure set forth above with respect to Example 1. Compounds whereinR₁=Br are prepared essentially according to the procedure of Example 2.

Example M + H m/z FABHRMS No. R₁ R₂ MF Requires m/z Ex. 3 —H 4-BrC₁₉H₁₆BrNO₂ 370.0428 370.0443 Ex. 4 —Br 4-Br C₁₉H₁₅Br₂NO₂ 447.9522447.9548 Ex. 5 —H 4-Cl C₁₉H₁₆ClNO₂ 326.0948 326.0893 Ex. 6 —Br 4-ClC₁₉H₁₅BrClNO₂ 404.0053 404.0035 Ex. 7 —H 3-F C₁₉H₁₆FNO₂ 310.1243310.1226 Ex. 8 —Br 3-F C₁₉H₁₅BrFNO₂ Ex. 9 —H 2-F C₁₉H₁₆FNO₂ 310.1231310.1243 Ex. 10 —Br 2-F C₁₉H₁₅BrFNO₂ 388.0348 388.0373NMR characterization of compounds of Examples 3–10

Ex. No. NMR Data Ex. 3 ¹H NMR (CDCl₃/300 MHz) δ: 7.43 (d, 2H); 7.40-7.33(m, 5H); 7.20-7.07 (m, 3H); 6.04-6.01 (m, 1H); 6.00-5.92 (m, 1H); 5.03(s, 2H); 4.98 (s, 2H) Ex. 4 ¹H NMR (CDCl₃/300 MHz) δ: 7.50-7.15 (m,10H); 6.06 (d, 1H); 5.20 (s, 2H), 5.10 (s, 2H) Ex. 5 ¹H NMR (CDCl₃/300MHz) δ: 7.40-7.32 (m, 5H); 7.24 (AB quartet, 4H); 7.10 (d, 1H);6.03-6.00 (m, 1H); 5.98-5.92 (m, 1H); 5.03 (s, 2H); 4.99 (s, 2H) Ex. 6¹H NMR (CDCl₃/300 MHz): 7.43-7.20 (m, 10H); 6.08 (d, H1); 5.20 (s, 2H);5.10 (s, 2H) Ex. 7 ¹H NMR (CDCl₃/300 MHz) δ: 7.45-7.25 (m, 5H); 7.12 (d,1H); 7.07-6.93 (m, 4H); 6.04-6.02 (m, 1H); 6.00-5.94 (m, 1H); 5.08 (s,2H); 5.00 (s, 2H) Ex. 8 ₁H NMR (CDCl₃/300 MHz) δ: 7.43-7.25 (m, 6H);7.21 (d, 1H); 7.10-6.93 (m, 3H); 6.08 (d, 1H); 5.22 (s, 2H); 5.12 (s,2H) Ex. 9 ¹H NMR (CDCl₃/300 MHz) δ: 7.43-7.00 (m, 10H); 6.01-5.92 (m,2H); 5.10 (s, 2H); 4.99 (s, 2H) Ex. 10 ¹H NMR (CDCl₃/300 MHz): 7.52 (dof t, 1H); 7.44-7.26 (m, 7H); 7.15-7.00 (m, 2H); 6.03 (d, 1H); 5.20 (s,2H); 5.15 (s, 2H)

Example 11 4-(benzyloxy)-3-bromopyridin-2(1H)-one

The material of Example 11 was prepared according to the procedure ofExample 2. ¹H NMR (CDCl₃/300 MHz) δ: 7.50-7.30 (m, 6H); 6.20 (d, 1H);5.24 (s, 2H).

Anal. Calcd for C₁₂H₁₀BrNO₂ (0.3H₂O): C, 50.48; H, 3.74; N, 4.91. Found:C, 50.79; H, 3.41; N, 4.82.

Examples 12-19

The compounds of Examples 12-19 are prepared essentially according tothe procedures set forth above for Example 1. Compounds wherein R₁=Brare prepared essentially according to the procedure of Example 2.

Exam- ple M + H FABHRMS No. R₁ R₂ MF Requires m/z Ex. 12 —Br 4-benzyloxyC₂₆H₂₂BrNO₃ 476.0861 476.0854 Ex. 13 —H 4-CO₂Me C₂₁H₁₉NO₄ 350.1392350.1391 Ex. 14 —Br 4-CO₂Me C₂₁H₁₈BrNO₄ 428.0497 428.0480 Ex. 15 —Br4-CO₂H C₂₀H₁₆BrNO₄ 414.0341 414.0360 Ex. 16 —H 4-CN C₂₀H₁₆N₂O₂ 317.1290317.1270 Ex. 17 —Br 4-CN C₂₀H₁₅BrN₂O₂ 395.0395 395.0376 Ex. 18 —H4-tButyl C₂₃H₂₅NO₂ 348.1964 348.1949 Ex. 19 —Br 4-tButyl C₂₃H₂₄BrNO₂426.1069 426.1023NMR characterization of compounds of Examples 12–19

Ex. No. NMR Data Ex. 12 ¹H NMR (CDCl₃/300 MHz): 7.45-7.15 (m, 13H); 6.92(d, 2H); 6.01 (d, 1H); 5.20 (s, 2H); 5.08 (s, 2H); 5.03 (s, 2H) Ex. 13¹H NMR (CDCl₃/300 MHz): 8.00 (d, 2H); 7.40-7.25 (m, 7H); 7.10 (d, 1H);6.03-6.01 (m, 1H); 6.00-5.93 (m, 1H); 5.12, (s, 2H); 5.00 (s, 2H); 3.95(s, 3H) Ex. 14 ¹H NMR (CDCl₃/300 MHz): 8.00 (d, 2H); 7.42-7.31 (m, 7H);7.23 (d, 1H); 6.08 (d, 1H); 5.22 (d, 2H); 5.20 (s, 2H); 3.95 (s, 3H) Ex.15 ¹H NMR (DMSO-d₆/300 MHz): 8.00-7.80 (m, 3H); 7.53-7.27 (m, 7H); 6.50(d, 1H); 5.32 (s, 2H); 5.20 (s, 2H) Ex. 16 ¹H NMR (CDCl₃/300 MHz) δ:7.60 (d, 2H); 7.42-7.30 (m, 7H); 7.13 (d, 1H); 6.05-5.98 (m, 2H); 5.11(s, 2H); 5.00 (s, 2H) Ex. 17 ¹H NMR (CDCl₃/300 MHz) δ: 7.61 (d, 2H);7.48-7.30 (m, 6H); 7.23 (d, 2H); 6.12 (d, 1H); 5.22 (s, 2H); 5.20 (s,2H) Ex. 18 ¹H NMR (CDCl₃/300 MHz): 7.40-7.28 (m, 7H); 7.20 (d, 2H); 7.10(d, 1H); 6.02 (d, 1H); 5.97-5.90 (m, 1H); 5.02 (d, 2H); 4.98 (d, 2H) Ex.19 ¹H NMR (CDCl₃/300 MHz) δ: 7.43-7.20 (m, 10H); 6.02 (d, 1H); 5.20 (s,2H); 5.10 (s, 2H); 1.30 (s, 9H)

Example 20 4-(benzyloxy)-3-bromo-1-ethylpyridin-2(1H)-one

To 4-benzyloxy-2(1H)-pyridone (1.0 g, 0.005 mol) and potassium carbonate(1.0 g, 0.007 mol) in DMF (10 mL) was added bromoethane (0.82 mL, 0.011mol). Contents were heated at 75° C. overnight. Contents were allowed tocool and partitioned between EtOAc and water. The EtOAc layer was driedover MgSO₄, filtered, and concentrated in vacuo leaving a waxy solid,which was recrystallized from EtOAc/hexanes to give a white solid (720mg). To the white solid (700 mg, 0.003 mol) in glacial acetic acid (10mL), bromine (0.17 mL, 0.00325 mol) in glacial acetic acid (5 mL) wasadded dropwise at 15° C. Contents were stirred one hour at roomtemperature and a yellow solid (1.1 g) was filtered. The solid waspartitioned between EtOAc and 2.5N sodium hydroxide. The EtOAc layer wasdried over MgSO₄, filtered, and concentrated in vacuo leaving acolorless oil (710 mg), which solidified. FABHRMS m/z 310.0267 (M+H,C₁₄H₁₅BrNO₂ requires 310.0263). ¹H NMR (CDCl₃/300 MHz) δ: 7.45-7.30 (m,6H); 7.22 (d, 1H); 6.07 (d, 1H); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t,3H).

Anal. Calcd for C₁₄H₁₄BrNO₂: C, 54.56; H, 4.58; N, 4.55. Found: C,54.21; H, 4.38; N, 4.43.

Example 21 3-bromo-4-hydroxy-1-(4-hydroxybenzyl)pyridin-2(1H)-one

The material of Example 12 (120 mg, 0.25 mmol) and 10% palladium/carbon(30 mg) in glacial acetic acid (2 mL) were shaken at 55 lbs of hydrogenfor 4 hours. Contents were filtered and the filtrate was concentrated invacuo leaving an oil. FABHRMS m/z 295.9952 (M+H, C₁₂H₁₁BrNO₃ requires295.9922). ¹H NMR (DMSO-d₆/300 MHz) δ: 11.40 (br s, 1H); 9.40 (br s,1H); 7.60 (d, 1H); 7.10 (d, 2H); 6.70 (d, 2H); 6.02 (d, 1H); 4.93 (s,2H).

Anal. Calcd for C₁₂H₁₀BrNO₃ (1.4H₂O): C, 44.85; H, 4.02; N, 4.36. Found:C, 45.07; H, 4.10; N, 4.35.

Example 22 4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one hydrobromide

To 4-benzyloxy-2(1H)-pyridone (1.0 g, 0.005 mol) and potassium carbonate(760 mg, 0.0055 mol) in DMF (10 mL) was added methyl iodide (0.342 mL,0.0055 mol). Contents were stirred overnight. Contents were partitionedbetween EtOAc and water. The EtOAc layer was dried over MgSO₄, filtered,and concentrated in vacuo leaving a white solid (960 mg).

To the white solid (332 mg, 0.0015 mol) in glacial acetic acid (10 mL),bromine (256 mg, 0.0016 mol) in glacial acetic acid (5 mL) was addeddropwise at 15° C. Contents were stirred one hour at room temperatureand the desired was filtered as a white solid, 262 mg (59% yield). mp105.3-105.6° C. FABHRMS m/z 296.0097 (M+H, C₁₃H₁₃BrNO₂ requires296.0110). ¹H NMR (CDCl₃/300 MHz) δ: 7.45-7.30 (m, 6H); 7.22 (d, 1H);6.07 (d, 1H); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H).

Anal. Calcd for C₁₃H₁₂BrNO₂ (HBr, 0.3H₂O): C, 41.04; H, 3.60; N, 3.68.Found: C, 41.00; H, 3.87; N, 3.52.

Example 23 4-(benzyloxy)-3-bromo-1-methylpyridin-2(1H)-one

The material of Example 22 was partitioned between EtOAc and 2.5N sodiumhydroxide. The EtOAc layer was dried over MgSO₄, filtered, andconcentrated in vacuo leaving a red oil, which solidified FABHRMS m/z294.0112 (M+H, C₁₃H₁₃BrNO₂ requires 294.0130). ¹H NMR (CDCl₃/300 MHz):7.45-7.30 (m, 6H); 7.22 (d, 1H); 6.07 (d, 1H); 5.20 (s, 2H); 4.00 (q,2H); 1.32 (t, 3H).

Anal. Calcd for C₁₃H₁₂BrNO₂: C, 53.08; H, 4.11; N, 4.76. Found: C,53.06; H, 4.20; N, 4.74.

Example 244-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}-N′-hydroxybenzenecarboximidamide

The material of Example 17 (500 mg, 0.00127 mol), hydroxylaminehydrochloride (90 mg, 0.0013 mol) and sodium bicarbonate (109 mg) wererefluxed in ethanol (15 mL) overnight. Contents were allowed to cool anda solid was filtered and washed with water to give the desired as awhite solid, 447 mg, (82% yield). mp 210.2-212.2° C. FABHRMS m/z428.0634 (M+H, C₂₀H₁₉BrN₃O₃ requires 428.0610). ¹H NMR (DMSO-d₆/300MHz): 9.66 (s, 1H); 7.98 (d, 1H); 7.65 (d, 2H); 7.55-7.35 (m, 5H); 7.30(d, 2H); 6.54 (d, 1H); 5.82 (s, 2H); 5.35 (s, 2H); 5.17 (s, 2H).

Anal. Calcd for C₂₀H₁₈BrN₃O₃: C, 56.09; H, 4.24; N, 9.81. Found: C,55.92; H, 4.01; N, 9.52.

Example 254-(benzyloxy)-3-bromo-1-(piperidin-4-ylmethyl)pyridin-2(1H)-onehydrochloride

To the material of Example 11 (924 mg, 0.0033 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 3.6 mL).Contents were stirred one hour before adding dropwise a solution of4-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butylester (J. Labelled Compd, Radiopharm, 38(7), 1996, 595-606) (1.0 g,0.0036 mol) in DMF (5 mL). Contents were heated at 75° C. overnight.Contents were allowed to cool and poured into water (100 mL). A solidwas filtered and recrystallized from EtOAc to give white crystals (546mg). The white crystals were refluxed in 4 N HCl/dioxane (10 mL) for 3hours, allowed to cool and filtered to give the desired as a whitesolid, 415 mg (30% yield). mp 207.9° C. FABHRMS m/z 377.0852 (M+H,C₁₈H₂₃BrClN₂O₂ requires 377.0865). ¹H NMR (DMSO-d₆/300 MHz) δ: 8.90 (br,1H); 8.64 (br, 1H); 7.80 (d, 1H); 7.50-7.30 (m, 5H); 6.48 (d, 1H); 5.30(s, 2H); 3.83 (d, 2H); 3.20 (d, 2H); 2.88-2.64 (m, 2H); 2.10-1.90 (m,1H); 1.60 (d, 2H); 1.50-1.40 (m, 2H).

Anal. Calcd for C₁₈H₂₂BrClN₂O₂ (0.3H₂O): C, 51.58; H, 5.43; N, 6.68.Found: C, 51.59; H, 5.42; N, 6.81.

Example 26 4-(benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one

The material of Example 26 was prepared according to the procedure ofExample 1. FABHRMS m/z 360.1213 (M+H, C₂₀H₁₇F₃NO₂ requires 360.1211). ¹HNMR (CDCl₃/300 MHz) δ: 7.60 (d, 2H); 7.41-7.30 (m, 7H); 7.13 (d, 1H);6.05-6.01 (m, 1H); 6.00-5.95 (m, 1H); 5.13 (s, 2H); 5.00 (s, 2H).

Anal Calcd for C₂₀H₁₆F₃NO₂: C, 66.85; H, 4.49; N, 3.90. Found: C, 66.64;H, 4.26; N, 3.93.

Example 274-(benzyloxy)-3-bromo-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-one

The material of Example 27 was prepared according to the procedure ofExample 2. FABHRMS m/z 438.0308 (M+H, C₂₀H₁₆BrF₃NO₂ requires 438.0316).¹H NMR (CDCl₃/300 MHz) δ: 7.65-7.20 (m, 10H); 6.13-6.03 (m, 1H);5.30-5.13 (m, 4H).

Anal. Calcd for C₂₀H₁₅BrF₃NO₂: C, 54.81; H, 3.45; N, 3.20. Found: C,54.69; H, 3.34; N, 3.19.

Example 284-(benzyloxy)-3-bromo-1-(piperidin-3-ylmethyl)pyridin-2(1H)-onehydrochloride

To the material of Example 11 (3.1 g, 0.011 mol) in DMF (20 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 12 mL).Contents were stirred one hour before adding dropwise a solution of3-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butylester (Bioorg. Med. Chem. Lett, 8(13), 1998, 1595-1600) (4.2 g, 0.015mol) in DMF (5 mL). Contents were heated at 75° C. overnight. Contentswere allowed to cool, poured into water (100 mL) and a solid wasfiltered. The solid was stirred in 4 N HCl/dioxane (15 mL) for 3 hoursand filtered to give the desired as a white solid, 752 mg (18% yield).mp 138.1-139.2° C. FABHRMS m/z 377.0859 (M+H, C₁₈H₂₂BrN₂O₂ requires377.0865). ¹H NMR (DMSO-d₆/300 MHz): 9.50-9.10 (br, 2H); 8.00 (d, 1H);7.50-7.30 (m, 5H); 6.93 (d, 1H); 5.30 (s, 2H); 4.30-3.90 (m, 3H);3.40-3.10 (m, 3H); 2.80-2.50 (m, 3H); 2.40-2.00 (m, 1H); 1.90-1.60 (m,4H); 1.40-1.10 (m, 1H).

Anal. Calcd for C₁₈H₂₁BrN₂O₂ (2HCl, 0.25H₂O): C, 47.55; H, 5.21; N,6.16. Found: C, 47.48; H, 5.46; N, 6.27.

Example 29 4-(benzyloxy)-3-bromo-1-(2-thien-3-ylethyl)pyridin-2(1H)-one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL).Contents were stirred one hour before adding dropwise a solution ofmethanesulfonic acid 2-thiophen-3-yl-ethyl ester (J.A.C.S, 109(6), 1987,1858-1859) (412 mg, 0.002 mol) in DMF (5 mL). Contents were heated at75° C. overnight. Contents were allowed to cool, poured into water (100mL), and extracted into EtOAc, dried over MgSO₄, filtered, andconcentrated in vacuo leaving a light yellow oil. The oil was purifiedby silica gel chromatography eluting with 50% EtOAc/hexanes to give thedesired as a white solid, 199 mg (28% yield). mp 134.0-134.3° C.

FABHRMS m/z 390.0144 (M+H, C₁₈H₁₇BrNO₂S requires 390.0163). ¹H NMR(CDCl₃/300 MHz): 7.43-7.20 (m, 6H); 6.92-6.80 (m, 3H); 5.90 (d, 1H);5.20 (s, 2H); 4.13 (t, 2H); 3.10 (t, 2H).

Anal. Calcd for C₁₈H₁₆BrNO₂S: C, 55.39; H, 4.13; N, 3.59. Found: C,55.21; H, 3.87; N, 3.52.

Example 30 4-(benzyloxy)-3-bromo-1-(2-thien-2-ylethyl)pyridin-2(1H)-one

The title compound was prepared essentially according to the procedureof Example 29. mp 128.0-129.5° C. FABHRMS m/z 390.0160 (M+H,C₁₈H₁₇BrNO₂S requires 390.0163). ¹H NMR (CDCl₃/300 MHz) δ: 7.48-7.30 (m,5H); 7.12 (d, 1H); 6.95-6.80 (m, 2H); 6.75-6.68 (m 1H); 5.95 (d, 1H);5.20 (s, 2H); 4.16 (t, 2H); 3.30 (t, 2H).

Anal. Calcd for C₁₈H₁₆BrNO₂S: C, 55.39; H, 4.13; N, 3.59. Found: C,55.06; H, 4.01; N, 3.56.

Example 314-(benzyloxy)-3-bromo-1-[3-(trifluoromethyl)benzyl]pyridin-2(1H)-one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) wasadded dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL).Contents were stirred one hour before adding dropwise a solution of3-trifluoromethylbenzyl bromide (478 mg, 0.002 mol) in DMF (5 mL).Contents were heated at 75° C. for 2 hours. Contents were allowed tocool, poured into water (100 mL), and extracted with EtOAc, which wasdried over MgSO₄, filtered, and concentrated in vacuo leaving a whitesolid. FABHRMS m/z 438.0301 (M+H, C₂₀H₁₆BrF₃NO₂ requires 438.0316). ¹HNMR (CDCl₃/300 MHz): 7.60-7.20 (m, 10H); 6.10 (d, 1H); 5.14 (s, 2H);5.20 (s, 2H).

Anal. Calcd for C₂₀H₁₅BrF₃NO₂: C, 54.81; H, 3.45; N, 3.20. Found: C,54.81; H, 3.36; N, 3.13.

Example 324-(benzyloxy)-3-bromo-1-[2-(trifluoromethyl)benzyl]pyridin-2(1H)-one

The material of Example 32 was prepared according to the procedure ofExample 31.

FABHRMS m/z 438.0280 (M+H, C₂₀H₁₆BrF₃NO₂ requires 438.0316). ¹H NMR(CDCl₃/300 MHz) δ: 7.68 (d, 1H); 7.55-7.20 (m, 8H); 7.15 (d, 1H); 6.10(d, 1H); 5.40 (s, 2H); 5.13 (s, 2H).

Anal. Calcd for C₂₀H₁₅BrF₃NO₂: C, 54.81; H, 3.45; N, 3.20. Found: C,54.48; H, 3.36; N, 3.17.

Example 33 4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one

The material of Example 33 was prepared according to the procedure ofExample 1.

FABHRMS m/z 376.1158 (M+H, C₂₀H₁₇F₃NO₃ requires 376.1161). ¹H NMR(CDCl₃/300 MHz) δ: 7.40-7.05 (m, 10H); 6.05-5.95 (m, 2H); 5.06 (s, 2H);4.98 (s, 2H).

Anal. Calcd for C₂₀H₁₆F₃NO₃: C, 64.00; H, 4.30; N, 3.73. Found: C,63.97; H, 4.26; N, 3.57.

Example 344-(benzyloxy)-3-bromo-1-[4-(trifluoromethoxy)benzyl]pyridin-2(1H)-one

The material of Example 34 was prepared according to the procedure ofExample 2.

FABHRMS m/z 454.0240 (M+H, C₂₀H₁₆BrF₃NO₃ requires 454.0266). ¹H NMR(CDCl₃/300 MHz) δ: 7.45-7.10 (m, 10H); 6.08 (d, 1H); 5.20 (s, 2H); 5.12(s, 2H).

Anal. Calcd for C₂₀H₁₅BrF₃NO₃: C, 52.88; H, 3.33; N, 3.08. Found: C,52.53; H, 3.09; N, 2.92.

Example 35 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one

Step 1: Preparation of 1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one

4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol,21.4 g) were added to water (800 mL) and heated to reflux with stirringfor 2 hours. After cooling to room temperature, a light brown solid wascollected by filtration. (33.4 g, 77%): ¹H NMR (DMSO-d₆/300 MHz) δ: 10.5(s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2(s, 3H). ESHRMS m/z 216.100 (M+H, C₁₂H₁₃NO₂ requires 216.102).

Step 2: Preparation of 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one

1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (10 mmol, 2.15 g),dichloromethane (100 mL), benzylbromide (11 mmol, 1.88 g), sodiumhydroxide (2.5 N, 20 mmol, 8 mL), and benzyltriethylammonium chloride(0.5 g) were vigorously stirred at room temperature for 16 h.Hydrochloric acid (1 N) was added until the mixture produced an acidicreaction to pH paper. The mixture was then extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated. The product wasobtained by flash chromatography eluting with ethyl acetate:hexanes(1:2). The appropriate fractions were concentrated to a clear oil. (1.3g, 43%): ¹H NMR (DMSO-d₆/300 MHz) δ: 7.4-7.1 (m, 10H), 6.0 5.9 (m, 2H),5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 306.147 (M+H,C₂₀H₁₉NO₂ requires 306.149).

Example 36 1-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(1H)-one

The product from example 35,1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g),acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirredat room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise withstirring. After ½ hour, water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with saturated aqueous sodium bicarbonate solution andbrine. After drying over magnesium sulfate and concentrating, themixture was purified by flash column chromatography eluting with ethylacetate:hexanes (1:2). The appropriate fractions were concentrated toyield a light oil. (1.0 g, 62%): ¹H NMR (DMSO-d₆/300 MHz) 7.4-7.0 (m,10H), 6.5 (s, 1H), 5.29 (s, 2H), 5.27 (s, 2H), 2.2 (s, 3H). ESHRMS m/z384.057 (M+H, C₂₀H₁₈NO₂Br requires 384.060).

Example 37 1-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-one

The product from example 35,1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g),acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirredat room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise withstirring. After ½ hour, water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined organics werewashed with saturated aqueous sodium bicarbonate solution and brine.After drying over magnesium sulfate and concentrating, the mixture waspurified by flash column chromatography eluting with ethylacetate:hexanes (1:2). The appropriate fractions were concentrated toyield a white solid. (0.3 g, 15%): ¹H NMR (DMSO-d₆/300 MHz) 7.5-7.0 (m,10H), 5.42 (s, 2H), 5.07 (s, 2H), 2.45 (s, 3H). ESHRMS m/z 463.966 (M+H,C₂₀H₁₇NO₂Br₂ requires 463.968).

Example 38 1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Step 1: Preparation of 1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl4-bromobenzenesulfonate

1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (from example 35) (10 mmol,2.15 g), N,N′-dimethylformamide (30 mL), potassium carbonate (20 mmol,2.76 g), and 4-bromobenzenesulfonyl chloride (10 mmol, 2.55 g) werestirred at room temperature for 16 hours. Hydrochloric acid (1N) wasadded until the mixture was acidic to pH paper. Brine (50 mL) was addedand the mixture extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were washed with brine and dried over magnesiumsulfate, and filtered. After concentrating, the material was purified byflash column chromatography eluting with ethyl acetate:hexanes (1:2).The appropriate fractions were concentrated to a clear oil, whichsolidified upon standing several days to a white solid. (3.3 g, 76%): ¹HNMR (DMSO-d₆/400 MHz) 7.9 (m, 4H), 7.32-7.00 (m, 5H), 7.3 (m, 1H), 6.12(d, J=2.4 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.20 (s, 2H), 2.2 (s, 3H).ESHRMS m/z 436.002 (M+H, C₁₉H₁₆NO₄SBr requires 436.004).

Step 2: Preparation of1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one

1-benzyl 6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate(3.0 mmol, 1.3 g), N,N′-dimethylformamide (30 mL), 3-chlorobenzylalcohol (3.0 mmol, 0.43 g), and sodium hydroxide (60%, 3.3 mmol, 0.13 g)were stirred at room temperature under nitrogen for 4 hours.Hydrochloric acid (1 N, 10 mL) was added and the mixture extracted withethyl acetate (3×25 mL). The combined organic extracts were washed withsaturated aqueous sodium bicarbonate solution and brine. After dryingover magnesium sulfate and concentrating, the mixture was purified byflash column chromatography eluting with ethyl acetate:hexanes (1:1) toobtain a light yellow oil. (14.3 g, 64%): ¹H NMR (DMSO-d₆/300 MHz) δ:7.4-7.0 (m, 10H), 6.0-5.8 (m, 2H), 5.2 (s, 2H), 5.0 (s, 2H), 2.1 (s,3H). ESHRMS m/z 340.110 (M+H, C₂₀H₁₈NO₂Cl requires 340.110).

Example 391-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one

The product of example 38 (SC-83316),1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.91 mmol,310 Mg), acetic acid (20 mL), and sodium acetate (0.91 mmol, 80 Mg) werestirred at room temperature when bromine (0.91 mmol, 145 Mg) was added.After stirring for one hour, the mixture was concentrated, dissolved inethyl acetate, and washed successively with saturated aqueous sodiumbicarbonate solution, brine, and water. After drying over magnesiumsulfate and concentrating, the product was recrystallized fromtetrahydrofuran/hexanes to yield a white solid. (240 Mg, 63%): ¹H NMR(DMSO-d₆/300 MHz) 7.6-7.0 (m, 10H), 6.5 (s, 1H), 5.33 (s, 2H), 5.33 (s,2H), 2.3 (s, 3H). ESHRMS m/z 420.019 (M+H, C₂₀H₁₇NO₂BrCl requires420.019).

Example 40 1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared essentially as described in claim 1. mp151.6-152.0° C. ¹H NMR (CDCl₃/300 MHz) δ: 7.31 (m, 8H), 7.12 (d, 1H,J=7.45 Hz), 6.13 (d, 1H, J=2.42 Hz), 5.90 (dd, 1H, J=2.62 Hz), 5.22 (s,2H), 5.10 (s, 2H). ESHRMS m/360.0551 (M+H C₁₉H₁₅Cl₂NO₂ requires360.0558).

Example 41 1-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one

1-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(1H)-one (0.400 g, 1.11mmol) was dissolved in acetic acid (10 mL) Sodium acetate (0.091 g, 1.11mmol was added, and the mixture was cooled to 15° C. Bromine (0.195 g,1.22 mmol) was added via syringe. The reaction stirred at roomtemperature for 2 hours. Water (15 mL) was added, and the mixturetransferred to a separatory funnel. Ethyl acetate (50 mL) was added andthe layers were separated. The organic phase was washed with aqueousNaHCO₃ (2×25 mL), dried over MgSO₄, filtered, and evaporated to yield awhite solid. ¹HNMR (CDCl₃/300 MHz) δ: 7.34 (m, 9H), 6.24 (d, 1H, J=7.65Hz), 5.37 (s, 2H), 5.18 (s, 2H). ESHRMS m/z 439.9646 (M+H C₁₉H₁₄BrCl₂NO₂requires 439.9641).

Example 42 1-Benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 1. mp 124.6-125.0° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.36(m, 9H), 7.14 (d, 1H, J=7.65 Hz), 6.04 (d, 1H, J=2.62 Hz), 5.98 (d, 1H,J=2.82 Hz), 5.10 (s, 2H), 5.09 (s, 2H). ESHRMS m/z 326.0950 (M+HC₁₉H₁₆ClNO₂ requires 326.0948).

Anal. Calc'd. for C₁₉H₁₆ClNO₂: C, 70.05; H, 4.95; N, 4.30; Cl, 10.88.Found: C, 69.87; H, 4.74; N, 4.42, Cl, 11.08.

Example 43 1-Benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 143.3-145.5° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.63(d, 2H, J=1.81 Hz), 7.44 (m, 9H), 6.06 (d, 1H, J=7.65 Hz), 5.29 (s, 2H),5.17 (s, 2H). ESHRMS m/z 406.0036 (M+H C₁₉H₁₅BrClNO₂ requires 406.0032).

Anal. Calc'd. for C₁₉H₁₅ClBrNO₂: C, 56.39; H, 3.74; N, 3.46; Cl, 8.76.Found: C, 56.01; H, 3.38; N, 3.36, Cl, 9.01.

Example 44 1-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 149.0-149.7° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.25(m, 10H), 6.04 (d, 1H, J=7.65 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 2.34 (s,3H). ESHRMS m/z 386.0583 (M+H C₂₀H₁₈BrNO₂ requires 386.0581).

Example 45 1-Benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 1. mp 95.5-95.7° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.34(m, 9H), 7.13 (d, 1H, J=7.45 Hz), 5.96 (m, 1H), 5.95 (d, 1H, J=7.45 Hz),5.09 (s, 2H), 4.96 (s, 2H). ESHRMS m/z 326.0977 (M+H C₁₉H₁₆ClNO₂requires 326.0948).

Example 46 1-Benzyl-4-[benzylthio]-3-bromopyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 180.6-182.1° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.33(m, 10H), 7.14 (d, 1H, J=7.45 Hz), 6.08 (d, 1H, J=7.45 Hz), 5.13 (s,2H), 4.15 (s, 2H). ESHRMS m/z 386.0211 (M+H C₁₉H₁₆BrNOS requires386.0214).

Example 47 1-Benzyl3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed in Example 2. mp 133.2-133.5° C. ¹HNMR (CDCl₃/300 MHz) δ: 7.81(d, 1H, J=7.65 Hz), 7.68 (d, 1H, J=7.65 Hz), 7.61 (t, 1H, J=7.65 Hz),7.38 (m, 7H), 6.01 (d, 1H, J=7.85 Hz), 5.39 (s, 2H), 5.16 (s, 2H) ESHRMSm/z 438.0313 (M+H C₂₀H₁₅BrF₃NO₂ requires 403.0316).

Example 48 1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one

A mixture of N,O-dibenzyl-2-pyridone (2.0 g, 6.87 mmol),N-iodosuccinimide (1.7 g), dichloroacetic acid (0.15 mL) in acetonitrile(40.0 mL) was heated at 65° C. under argon atmosphere for 3.5 h, withconstant stirring. The reaction mixture was concentrated to dryness, andthe residue was purified by silica gel flash chromatography usingEtOAc/hexanes 1:1 v/v to give the title compound 2.3 g (80%) as a flakywhite solid: ¹H-NMR (CDCl₃) δ: 7.4-7.2 (m, 10H), 7.19 (1H, d, J=7.6 Hz),5.95 (d, 1H, J=7.6 Hz), 5.2 (s, 1H), 5.15 (s, 2H); ER-MS m/z=418 (MH⁺);HR-MS m/z calcd C₁₉H₁₇NO₂418.0304, found 418.0277.

Example 49 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one

A solution of 1-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one (1.9 g,4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (20 0 mL)containing DMF (2.0 mL) was degassed using house vacuum and purged withargon. Then added PdCl₂(PPh₃)₂ (0.3 g) and the mixture was heated at 65°C. under argon atmosphere for 4 h, with stirring. The solvents weredistilled in vacuo, and the residue was triturated with EtOAc andfiltered through a pad of celite. The filtrate was concentrated and theresidue was purified by silica gel flash chromatography using 25% EtOAcin hexanes to give the title compound (0.75 g. 50%) as an orange coloredsolid.

¹H-NMR (CDCl₃) δ: 7.4-7.2 (m, 10H), 7.14 (d, 1H, J=7.6 Hz), 7.05 (dd,1H, J=12.0 Hz), 6.47 (dd, 1H, J=2.8 Hz), 6.07 (d, 1H, J=7.6 Hz), 5.4(dd, 1H, J=2.8 Hz), 5.13 (s, 4H); ER-MS m/z 418 (MH⁺); ER-MS m/z=318(MH⁺); HR-MS m/z calcd C₂₁H₂₀NO₂ 318.1494, found 318.1480.

Example 50 1-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one

To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g,1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%,0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h.The catalyst was removed by filtration, the filtrate was concentrated todryness and the resulting residue was purified by silica gel flashchromatography using EtOAc/hexanes (1:1, v/v) to afford the titlecompound (0.32 g, 64%) as a pale yellow powder: ¹H-NMR (CD₃OD) δ: 7.52(d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1 h, J=7.6 Hz), 5.18 (s,2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MSm/z=320 (MH⁺) HR MS m/z calcd C₂₁H₂₂NO₂ 320.1651, found 320.1648.

Example 513-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one

Step A Preparation of3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 2-chlorophenylisocyanate (3.0 g, 19.53 mmol), and diketene(3.3 g, 39.28 mmol) in toluene (10.0 mL) containing triethylamine (0.05mL) was heated to reflux for 6 h, under an atmosphere of argon. Toluenewas distilled in vacuo and the resulting residue was purified by silicagel flash chromatography using 25% EtOAc in hexanes as the eluent toafford the title compound (0.85 g, see ref: Heterocycles 27 (9), 2063,1988.) as a pale yellow solid: ¹H-NMR (CD₃OD) δ: 7.63 (m, 1H), 7.52 (m,2H), 7.4 (m, 1H), 6.14 (s, 1H), 2.58 (s, 3H), and 1.95 (s, 3H); ES-MSm/z=278 (MH⁺).

Step B Preparation of3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-methylpyridin-2(1H)-one

To a solution of3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.56 g,2.02 mmol) in DMF (5.0 mL), benzyl bromide (0.3 mL) and potassiumcarbonate (0.3 g, 2.16 mmol) were added. The mixture was stirred at roomtemperature for 3 h, and at 65° C. for 1 h under argon atmosphere. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL). Theorganic phase was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to dryness. The resulting residue was purified by silicagel flash chromatography using 50% EtOAc in hexanes to afford the titlecompound (0.58 g, 75%) as a pale yellow amorphous substance: ¹H-NMR(CD₃OD) δ: 7.65-7.3 (m, 9H), 6.5 (s, 1H), 5.31 (s, 2H), 2.42 (s, 3H),and 2.01 (s, 3H); ER-MS m/z=368 (MH⁺); HR-MS m/z calcd C₂₁H₁₉NO₃Cl,368.1060, found 368.1053.

Example 52 1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one

Step A Preparation of 1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one

A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS(0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperaturefor 1.5 h under argon atmosphere. It was diluted with dichloromethane(25 mL), cooled and filtered. The solids were washed withdichloromethane and dried in vacuo. The filtrate and the washings werecombined and washed with water, dried (Na₂SO₄), filtered, andconcentrated to dryness. The resulting residue was washed with EtOAc,and dried in vacuo to give a combined mass of 0.65 g of the titlecompound as a white powder: ¹H NMR (CD₃OD) δ: 7.54 (d, 1H, J=7.6 Hz),7.27 (m, 5H), 6.12 (d, 1H, J=7-6 Hz), 5.15 (s, 2H); ES-MS: m/z=280(MH⁺).

Step B Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a cold (−30° C.) suspension of1-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one (0.78 g, 2.8 mmol) indichloromethane (10.0 mL), was added triethylamine (0.6 mL, 4.28 mmol),followed by the addition of triflic anhydride (0.7 mL, 4.17 mmol). Theresulting mixture was stirred at −30° C. under argon atmosphere for 1 h.The reaction mixture was then poured into ice/water mixture (50 mL) andthe products were extracted with dichloromethane (2×25 mL). The combinedorganic extracts were washed with water (2×20 mL), dried (Na₂SO₄),filtered, and concentrated to dryness. The residue was dried in vacuo toafford the desired trifluorosulfonate (1.0 g) as a pale yellow solidwhich used as such in the next step: ¹H-NMR (CDCl₃) δ: 7.35 (m, 6H),6.26 (d, 1H, J=8.0 Hz); ¹⁹F-NMR (CDCl₃) δ: −73.73 ppm; ES-MS: m/z=412(MH⁺).

Step C Preparation of1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one

To a solution of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was addedphenylacetylene (0.4 mL) and degassed using house vacuum. The reactionflask was then purged with argon, added diisopropylethylamine (0.53 mL),and PdCl₂(PPh₃)₂ (0.35 g) were added. The resulting mixture was stirredat room temperature for 15 min and heated at 65° C. under an argonatmosphere for 3 h. The dark colored reaction mixture was concentratedin vacuo, and the residue was partitioned between EtOAc (50 mL) and 5%aqueous citric acid (25 mL). The organic extracts were washed withwater, dried (Na₂SO₄), filtered, and concentrated to dryness. Theresulting material was purified by silica gel flash chromatography using25% EtOAc in hexanes as the eluent. The appropriate fractions werecombined, concentrated under reduced pressure. ¹H NMR (CDCl₃) δ: 7.57(m, 2H), 7.38 (m, 8H), 7.21 (d, 1H, J=6.8 Hz), 6.25 (d, 1H, J=6.8 Hz),and 5.16 (d, 2H), ES-MS: m/z=364 (MH⁺); HR-MS m/z (MH⁺) calcd C₂₀H₁₅NOBr364.0337, found 364.0337.

Step D Preparation of1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H)-one

A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one (0.3g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL)and EtOH (10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi ina Fischer porter bottle for 45 min. The catalyst was removed byfiltration, and filtrate was concentrated. The resulting residue waspurified by silica gel flash chromatography using 25% EtOAc in hexanesas the eluent. The appropriate fractions (visualized under an UV lamp)were combined and concentrated under reduced pressure. ¹H-NMR (CD₃OD) δ:7.56 (d, 1H, J=6.8 Hz), 7.31-7.17 (m, 10H), 6.24 (d, 1H, J=6.8 Hz), 5.19(s, 2H), 2.96 (m, 2H), and 2.91 (m, 2H); ES-MS m/z=368 (MH⁺); HR-MS m/z(MH⁺) calcd C₂₀H₁₉NOBr 368.0650, found 368.0630.

Example 533-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one

The title compound was prepared essentially according to the procedureof Example 52. ¹H-NMR 6: (CD₃OD) δ: 7.35 (m, 1H), 7.31-7.16 (m, 5H),6.99 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 6.20 (s, 1H), 5.41 (s, 2H),2.94 (m, 4H), and 2.24 (s, 3H), ¹⁹F-NMR (CD₃OD) δ: −115.01 (m); ES-MS,m/z=400 (MH⁺); HR-MS; m/z calcd C₂₁H₂₀NOBrF 400.0712, found 400.0695.

Example 544-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

Step A Preparation of3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 2,6 dichlorophenylisocyanate (4.8 g, 0.025 mol), anddiketene (4.3 g, 0.05 mol) in toluene (15.0 mL) was heated to reflux for4 h under an atmosphere of argon. After removal of the solvent in vacuo,the residue was purified by silica gel flash chromatography usingEtOAc/hexanes (1:3 v/v). The appropriate fractions, as monitored by ESmass spectrometry (MH⁺ m/z=312) were combined and concentrated underreduced pressure. The resulting yellow solid (2.3 g) was furtherpurified by reverse-phase HPLC using 10 90% acetonitrile/water gradient(45 min) at a flow rate of 100 mL/min. The appropriate fractions, asmonitored by ES mass spectrometry (MH⁺ m/z=312) were combined andconcentrated to half the volume. The solid that separated was extractedwith EtOAc (2×25 mL). The combined extracts were washed with water,dried (Na₂SO₄), filtered, and concentrated to dryness to give the titlecompound (0.77 g) as a pale yellow powder: ¹H-NMR (CD₃OD) δ: 7.62 (m,2H), 7.52 (m, 1H), 6.19 (s, 1H), 2.59 (s, 3H), and 1.96 (6, 3H); ES-MSm/z=312 (MH⁺); HR-MS, m/z calc C₁₄H₁₂NO₃Cl₂ 312.0189, found 312.0214.

Step B Preparation of1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of3-acetyl-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 0.7g (0.002 mol) in n-butanol (3.0 mL) containing sulfuric acid (1.5 mL)was heated at 120° C. for 4 h. The dark reaction mixture was cooled,added ice/water (25 mL), and extracted with EtOAc (2×25 ml). Thecombined organic extracts were washed with water, dried (Na₂SO₄),filtered, concentrated under reduced pressure and the resulting materialwas purified by silica gel flash chromatography using 25% EtOAc inhexanes as the eluent to afford the title compound (0.14 g) as a paleyellow powder: ¹H-NMR (CD₃OD) δ: 7.6 (m, 2H), 7.48 (m, 1H), 6.10 (dd,1H), 5.78 (d, 1H, J=2.4 Hz), 1.91 (s, 3H); ES-MS m/z=270 (MH⁺); HR-MS,m/z calc C₁₂H₁₀NO₂Cl₂ 270.0083, found 270.0103.

Step C Preparation of4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

A mixture of 1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one(0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith water (10.0 mL) and extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with water, dried (Na₂SO₄), filtered,concentrated under reduced pressure and the resulting material waspurified by silica gel flash chromatography using 25% EtOAc in hexanesto afford the title compound (0.11 g) as a pale yellow syrup: ¹H-NMR(CD₃OD) δ: 7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, 1H, J=2.0 Hz), 6.01(d, 1H, J=2.0 Hz), 5.12 (s, 2H), and 1.93 (s, 3H); ES-MS m/z=360 (MH⁺);HR-MS, m/z calc C₁₉H₁₆NO₂Cl₂, 360.0553, found 360.0569.

Step D Preparation of4-(benzyloxy)-3-bromo-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one

A mixture of4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one (0.1 g,0.278 mmol) and N-bromosuccinimide (0.055 g, 0.3 mmol) in dichloroethane(3.0 mL) was stirred at room temperature for 1 h, and heated at 60° C.under argon for 30 min. The reaction mixture was then diluted withdichloroethane (15 mL), washed with water, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. ¹H NMR (CD₃OD) δ: 7.64 (m, 2H),7.55 (m, 3H), 7.38 (m, 3H), 6.65 (s, 1H), 5.34 (s, 2H), and 2.00 (s,3H); ES-MS m/z=439 (MH⁺); HR-MS, m/z calc C₁₉H₁₆NO₂Cl₂Br, 439.9635,found 439.9669.

Example 55 3-bromo-1-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(1H)-one

The title compound was prepared essentially according to the procedureof Example 52. ¹H-NMR (CD₃OD) δ: 7.58 (d, 1H, J=6.8 Hz), 7.4-7.0 (m,9H), 6.26 (d, 1H. J=6.8 Hz), 5.19 (s, 2H), 2.97 (m, 2H), and 2.90 (m,2H); ES-MS m/z=386 (MH⁺); HR-MS, m/z calc C₂₀H₁₈NOFBr, 386.0550, found386.0585.

Example 56 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

Step A Preparation of 1-benzyl-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

To a chilled solution of 1-benzyl-4-hydroxypyridin-2(1H)-one (0.375 g,1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine(0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride(0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogenatmosphere at 0° C. for 30 min then at room temperature for 1 h. Thereaction was monitored by TLC (5% methanol in dichloromethane). Thesolvent was removed under reduced pressure and the residue was washedwith 10% citric acid and extracted with EtOAc. The organic extracts werecombined, washed with water dried over anhydrous Na₂SO₄, and filtered.The solvent was removed under reduced pressure to afford a yellow syrup.The residue was purified by flash chromatography (silica gel) using 5%MeOH in CH₂Cl₂ to give the desired product (0.382 g, 61%) as a whitesemisolid.

MS and ¹H-NMR were consistent with the desired structure. ¹H NMR(d₆-DMSO, 400 MHz) δ: 7.8 (d, 1H), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s,2H), 3.29 (s, 3H); HR-MS (ES) m/z calcd for C₂₀H₁₈N₂O₃ (MH⁺)=335.1396,observed 335.1418.

Step B 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH₂Cl₂ (7 mL)was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction wasstirred overnight at room temperature under nitrogen atmosphere. Thereaction mixture was purified by flash chromatography (silica gel) usingEtOAc/hexanes (1:1 v/v). The appropriate fractions were collectedaccording to ES MS (M+H 413) and concentrated. The dried product showedabout 14% of di-brominated product by analytical HPLC. The compoundswere separated by reverse phase HPLC using a 10-90% acetonitrile inwater, 30 min gradient at a 100 mL/min flow rate, to afford (afterlyophilization) the salt of the desired compound. The salt was dilutedin EtOAc and washed with NaHCO₃. The organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated to afford the desiredcompound (0.271 g, 58%) as a beige solid.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR(d₆-DMSO, 400 Hz) δ: 7.83 (d, 1H), 7.39 (m, 10H), 6.48 (s, 1H), 5.12 (s,2H), 3.33 (s, 3H); HR-MS (ES) m/z calcd for C₂₀H₁₇O₃Br (MH⁺)=413.0495,observed 413.0496.

Example 57 4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one

Step A Preparation of4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one

Heated a reaction mixture of4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) inanhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1mmol) under nitrogen atmosphere at 65° C. for 4 h. The reaction mixturewas concentrated under reduced pressure and the residue was purified byflash chromatography (silica gel) using EtOAc/hexanes (1:1 v:v). Theappropriate fractions were collected according to ES MS (M+H 436) andwashed with Na₂SO₃ to remove the color impurities. The fractions wereconcentrated under reduced pressure and dried in vacuo to afford thedesired product (6.15 g, 90%) as a light yellow solid.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.73 (d, 1H), 7.47 (d, 2H), 7.39 (m, 4H), 7.08 (m, 3H), 6.39(d, 1H), 5.29 (s, 2H), 5.19 (s, 2H); HR-MS (ES) m/z calcd forC₁₉H₁₅NO₂FI (MH⁺)=436.0210, observed 436.0196.

Step B Preparation of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one

Degassed a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (2.01 g, 4.62mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere.Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. Thereaction mixture was chilled in an ice bath for 15 minutes before addingbistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprousiodide (0.2 g). The reaction was stirred at room temperature for 30 minbefore heating at 60° C. under an atmosphere of argon for 2 h. Thereaction mixture was filtered through a bed of celite and the filtratewas concentrated under reduced pressure. The dark brown residue wasdiluted with CH₂Cl₂ (100 mL) and washed with water. The organic extractswere combined, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The dark brown residue was purified by flashchromatography (silica gel) using 30% EtOAc in hexane. The appropriatefractions were combined and concentrated under reduced pressure toafford the desired product (1.34 g, 72%) as a light yellow solid.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.74 (d, 1H), 7.47 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.46(d, 1H), 5.26 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); HR-MS (ES) m/z calcdfor C₂₄H₂₄NO₂FSi (MH⁺)=406.1638, observed 406.1610.

Step C Preparation of4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one(1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C. was addedtetrabutylammonium fluoride (0.611 g, 1.93 mmol). The reaction wasstirred at 0° C. for 15 min then for 1 h at room temperature. Thereaction was concentrated under reduced pressure and the residue wasdiluted with EtOAc and washed with water. The organic extracts werecombined, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractionswere combined and concentrated under reduced pressure to afford thedesired product (0.779 g, 72%) as a gold solid.

MS and ¹H NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.73 (d, 1H), 7.43 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.45(d, 1H), 5.27 (s, 2H), 5.13 (s, 2H), 3.78 (s, 1H); HR-MS (ES) m/z calcdfor C₂₁H₁₆NO₂F (MH⁺)=334.1243, observed 334.1234.

Example 58 4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

Step A Preparation of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one

In a Fischer-Porter bottle, added a solution of4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.5 g, 14.56 mmol) inabsolute ethanol (20 mL). Flushed the solution with nitrogen then addedpalladium catalyst (1.05 g). Sealed bottle and evacuated system. Thesystem was purged with hydrogen gas (2×15 psi) to check for leaks. Thereaction was charged with hydrogen (35 psi) and stirred at roomtemperature for 45 min. The system was evacuated and flushed withnitrogen. The reaction was filtered and the catalyst was carefullywashed with fresh ethanol. The filtrate was concentrated under reducedpressure.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.54 (d, 1H), 7.32 (m, 1H), 7.06 (m, 3H), 6.05 (dd, 1H), 5.83(s, 1H), 5.09 (s, 2H); HR-MS (ES) m/z calcd for C₁₂H₁₀NO₂F(MH⁺)=220.0774, observed 220.0787.

Step B Preparation of4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one

Heated a reaction mixture of1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.005 g, 4.5 mmol) inbenzylamine (15 mL) at reflux (185° C.) under nitrogen atmosphere for 24h. The reaction was monitored by ES-MS (MH+ 309). The solvent wasremoved by vacuum distillation to give a yellow residue.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.31 (m, 7H), 7.03 (m, 3H), 5.98 (dd, 1H), 5.45 (s, 1H), 5.00(s, 2H), 4.30 (s, 2H); HR-MS (ES) m/z calcd for C₁₉H₁₇N₂OF.(MH⁺)=309.1403, observed 309.1375.

Step C Preparation of4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one(0.50 g, 1.62 mmol) in anhydrous CH₂Cl₂ (10 mL) was addedN-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred atroom temperature under a nitrogen atmosphere for 3 h. The reactionmixture was purified by flash chromatography (silica gel) using EtOAc inhexanes (1:1 v/v). The appropriate fractions were combined andconcentrated.

MS and ¹H-NMR were consistent with the desired structure. ¹H-NMR (CD₃OD,400 Hz) δ: 7.41 (d, 1H), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, 1H), 5.08(s, 2H), 4.53 (s, 2H); HR-MS (ES) m/z calcd for C₁₉H₁₆N₂OFBr(MH⁺)-387.0508, observed 387.0504.

Example 59

3-Bromo-1-cyclopropylmethyl-4-(4-fluorobenzyloxy)-1H-pyridin-2-oneStep 1. Preparation of 4-[(4-Fluorobenzyloxy]pyridine-1-oxide

To an ice-cold solution of sodium hydride (1.9 g, of a 60% dispersion inmineral oil, 46 mmol) in DMF (39 mL) was added 4-fluorobenzyl alcohol(5.1 mL, 46 mmol). The reaction mixture was warmed to room temperature,4 chloropyridine-1-oxide¹ (5.0 g, 39 mmol) was added, and the reactionmixture was stirred for 6 h. The reaction mixture was diluted with a 50%aqueous solution of brine, and extracted with CHCl₃ (7×50 mL). Thecombined organics were dried (MgSO₄), filtered, and concentrated underreduced pressure. Trituration with Et₂O afforded4-[(4-fluorobenzyloxy]pyridine-1-oxide as an off-white solid (9.1 g,90%), which was used in the next step without further purification orcharacterization.

Step 2. Preparation of 4-(4-Fluorobenzyloxy)-1H-pyridin-2-one

A solution of 4-[(4-fluorobenzyloxy]pyridine-1-oxide (6.4 g, 29 mmol) inacetic anhydride (97 mL) was heated at reflux for 3 h. The reactionmixture was cooled to room temperature and the solvent was removed underreduced pressure. The residue was diluted with 1:1 MeOH/water (34 mL),and the mixture was stirred at room temperature for 1 h. The solvent wasremoved under reduced pressure. Trituration with Et₂O/hexanes afforded4-(4-fluorobenzyloxy)-1H-pyridin-2-one as a brown solid (3.1 g, 48%): ¹HNMR (300 MHz, CDCl₃) δ 7.40-7.36 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.09 (t,J=7 Hz, 2H), 6.03 (dd, J=7, 3 Hz, 1H), 5.94 (d, J=3 Hz, 1H), 4.98 (s,2H).

Step 3. Preparation of 3-Bromo-4-(4-fluorobenzyloxy)-1H-pyridin 2-one

To an ice-cold solution of 4-(4-fluorobenzyloxy)pyridine-2(1H)-one (3.1g, 14 mmol) in AcOH (26 mL) was added a solution of bromine (0.79 mL, 15mmol) in AcOH (51 mL), and the reaction mixture was stirred at roomtemperature for 2 h. The solvent was removed under reduced pressure, andpurification by flash column chromatography (silica, 1:1 Et₂O/hexanes)to afford 3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-one as an orangesolid (0.78 g, 48%): MS APCI m/z 298 [M+H]⁺.

Step 4. Preparation of3-Bromo-1-cyclopropylmethyl-4-(4-fluorobenzyloxy)-1H-pyridin-2-one

To a solution of 3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-one (0.25 g,0.84 mmol) in DMF (13 mL) was added K₂CO₃ (0.33 g, 1.7 mmol) andcyclopropylmethyl bromide (0.14 g, 1.0 mmol), and the reaction mixturewas stirred at 110° C. for 2 h. The reaction mixture was cooled to roomtemperature, and the solvent was removed under reduced pressure. Theresidue was diluted with a 50% aqueous solution of brine, and extractedwith CHCl₃ (3×50 mL). The combined organics were washed with water andthen brine, dried (MgSO₄), filtered, and concentrated under reducedpressure. Purification by flash column chromatography (silica, 1:1EtOAc/hexanes) afforded3-bromo-1-cyclopropyl-methyl-4-(4-fluorobenzyloxy)-1H-pyridin-2-one as ayellow solid (0.12 g, 39%): mp 139-141° C.; ¹H NMR (300 MHz, CDCl₃) δ7.43-7.34 (m, 3H), 7.07 (t, J=9 Hz, 2H), 6.06 (d, J=6 Hz, 1H), 5.19 (s,2H), 3.82 (d, J=9 Hz, 2H), 1.26-1.23 (m, 1H), 0.62-0.57 (m, 2H),0.40-0.36 (m, 2H). ESHRMS m/z 352.0368 (M+H C₁₆H₁₆BrFNO₂ requires352.0343)

Examples 60-69

The compounds of Examples 60-69 are prepared essentially according tothe procedures set forth above for Example 59.

Example M + H ESHRMS No. R MF Requires m/z Ex. 60 pyridin-4- ylmethylEx. 61 pyridin-3- C₁₈H₁₄BrFN₂O₂ 489.0296 489.0281 ylmethyl Ex. 624-tert-butylbenzyl C₂₃H₂₃BrFNO₂ 444.0969 444.0971 Ex. 63 3-trifluoro-C₂₀H₁₄BrF₄NO₂ 456.0217 456.0202 methylbenzyl Ex. 64 Biphenyl-2-C₂₅H₁₉BrFNO₂ 464.0656 464.0656 ylmethyl Ex. 65 4-methoxybenzylC₂₀H₁₇BrFNO₃ 418.0449 418.0457 Ex. 66 4-cyanobenzyl C₂₀H₁₄BrFN₂O₂413.0295 413.0287 Ex. 67 4-trifluoro- C₂₀H₁₄BrF₄NO₂ 456.0217 456.0192methylbenzyl Ex. 68 Biphenyl-4- C₂₅H₁₉BrFNO₂ 464.0656 464.0653 ylmethylEx. 69 cyclohexylmethyl C₁₉H₂₁BrFNO₂ 394.0812 394.0797NMR characterization of compounds of Examples 12-19

Ex. No. NMR Data Ex. 60 ¹H NMR (300 MHz, CDCl₃) δ 8.57 (dd, J = 6, 3 Hz,2H), 7.43-7.38 (m, 2H), 7.16 (d, J = 6 Hz, 2H), 7.09 (t, J = 9 Hz, 2H),6.12 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.16 (s, 2H) Ex. 61 ¹H NMR (300MHz, CDCl₃) δ 8.58-8.55 (m, 2H), 7.75 (d, J = 6 Hz, 1H), 7.41-7.37 (m,2H), 7.31-7.26 (m, 2H), 7.12-7.04 (m, 2H), 5.17 (d, J = 6 Hz, 1H), 5.18(s, 2H), 5.16 (s, 2H) Ex. 62 ¹H NMR (300 MHz, MeOD) δ. 7.75 (d, 1H, J =9 Hz), 7.59 (t, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H), 7.22 (d, J = 9Hz, 2H), 7.06-6.99 (m, 2H), 6.52 (d, J = 9 Hz, 1H), 5.29 (s, 2H), 5.18(s, 2H), 1.28 (s, 9H) Ex. 63 ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.37 (m,5H), 7.29-7.26 (m, 2H), 7.08 (t, J = 7 Hz, 2H), 6.10 (d, J = 7 Hz, 1H),5.20 (s, 2H), 5.18 (s, 2H) Ex. 64 ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.27(m, 11H), 7.07 (t, J = 6 Hz, 2H), 6.72 (d, J = 7 Hz, 1H), 5.88 (d, J = 9Hz, 1H), 5.16 (s, 2H), 5.12 (s, 2H) Ex. 65 ¹H NMR (300 MHz, CDCl₃) δ7.38-7.36 (m, 2H), 7.27-6.84 (m, 3H), 7.08 (s, 2H), 6.86 (d, J = 7 Hz,2H), 6.01 (d, J = 6 Hz, 1H), 5.15 (s, 2H), 5.09 (s, 2H), 3.78 (s, 3H)Ex. 66 ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.61 (m, 2H), 7.42-7.37 (m, 4H),7.27-7.25 (m, 1H), 7.12-7.06 (m, 2H), 6.11 (d, J = 6 Hz, 1H), 5.19 (s,4H) Ex. 67 ¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, J = 6 Hz, 2H), 7.43- 7.37(m, 4H), 7.29-7.25 (m, 1H), 7.08 (t, J = 6 Hz, 2H), 6.08 (d, J = 9 Hz,1H), 5.20 (s, 2H), 5.18 (s, 2H) Ex. 68 ¹H NMR (300 MHz, CDCl₃) δ7.57-7.54 (m, 4H), 7.45-7.34 (m, 7H, 7.30-7.26 (m, 1H), 7.08 (t, J = 9Hz, 2H), 6.06 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.17 (s, 2H) Ex. 69 ¹HNMR (300 MHz, CDCl₃) δ 7.93 (d, J = 6 Hz, 1H), 7.45-7.40 (m, 2H),7.29-7.26 (m, 1H), 7.09 (t, J = 9 Hz, 2H), 6.50 (d, J = 6 Hz, 1H), 5.17(s, 2H), 4.14 (d, J = 6 Hz, 2H), 1.90-1.74 (m, 5H), 1.32-1.05 (m, 5H)

Example 70

{3-[3-Bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamicacid tert-butyl ester Step 1. Preparation of 3-Hydroxymethylbenzonitrile

To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38 mmol) in 1:1MeOH/THF (90 mL) was added NaBH₄ (1.6 g, 42 mmol), and the reactionmixture was stirred for 3 h. The reaction mixture was diluted withbrine, and the solvent was removed under reduced pressure. The residuewas dissolved in water, and the aqueous layer was extracted with Et₂O(3×100 mL). The combined organics were washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure to provide3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which wasused in the next step without further purification or characterization.

Step 2. Preparation of 3-(tert-Butyldimethylsilyloxymethyl)benzonitrile

To an ice-cold solution of 3-hydroxymethyl benzonitrile (4.95 g, 37mmol) in CH₂Cl₂ (47 mL) was added imidazole (5.1 g, 74 mmol), DMAP (0.45g, 3.7 mmol), and TBSCl (6.2 g, 41 mmol), and the reaction mixture wasstirred for 12 h. The reaction mixture was diluted with water, and theaqueous layer was extracted with CH₂Cl₂ (3×150 mL). The combinedorganics were washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide3-(tert-butyldimethylsilyloxymethyl)-benzonitrile (9-1 g, 99%) as aclear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.42 (d, J=6 Hz, 1H),7.35-7.28 (m, 1H), 4.75 (s, 2H), 0.94 (s, 9H), 0.11 (s, 6H).

Step 3. Preparation of 3-(tert-Butyldimethylsilyloxymethyl)benzylamine

To an ice-cold solution of3-(tert-butyldimethylsilyloxymethyl)benzonitrile (4.5 g, 18 mmol) in THF(47 mL) was added LiAlH₄ (27 mL, of a 1 M solution in THF, 27 mmol), andthe reaction mixture was stirred at reflux for 3 h. The reaction mixturewas cooled to 0° C., and the reaction was quenched with water (25 mL)and 15% NaOH in water (75 mL). The reaction mixture was filtered,concentrated under reduced pressure, and the residue was dissolved inEtOAc. The organic solution was washed with water and then brine, dried(MgSO₄), filtered, and concentrated under reduced pressure to provide3-(tert-Butyldimethylsilyloxymethyl)benzylamine (1.4 g, 30%) as a clearoil: ¹H NMR (300 MHz, CDCl₃) δ 7.22-7.10 (m, 4H), 4.57 (s, 2H), 3.74 (s,2H), 0.84 (s, 9H), 0.09 (s, 6H).

Step 4. Preparation of 3-(Hydroxymethyl)benzylcarbamic acid tert-butylester

To a solution of 3-(tert-butyldimethylsilyloxymethyl)benzylamine (1.4 g,5.5 mmol) and Et₃N (1.5 mL, 11 mmol) in CH₂Cl₂ (28 mL) was addeddi-tert-butyl dicarbonate (1.3 g, 5.8 mmol), and the reaction mixturewas stirred for 12 h. The reaction mixture was diluted with water andextracted with CH₂Cl₂ (3×100 mL). The combined organics were washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica, CH₂Cl₂) to afford3-(hydroxymethyl)benzylcarbamic acid tert-butyl ester as a yellow oil(1.4 g, 46%): ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.28 (m, 1H), 7.18 (d, J=8Hz, 1H), 7.12 (s, 1H), 7.08-7.01 (m, 1H), 4.60 (s, 2H), 4.04 (d, J=6 Hz,2H), 1.36 (s, 9H).

Step 5. Preparation of 3-(Bromomethyl)benzylcarbamic acid tert-butylester

To an ice-cold solution of 3-(hydroxymethylbenzyl)carbamic acidtert-butyl ester (0.7 g, 3.0 mmol) and CBr₄ (1.0 g, 3.1 mmol) in THF (14mL) was added Ph₃P (0.81 g, 3.1 mmol), and the reaction mixture wasstirred for 18 h. The reaction mixture was filtered, and concentratedunder reduced pressure. Purification by flash column chromatography(silica, eluent 5:95 to 15:85 EtOAc/hexanes) to afford the3-(bromomethyl)benzyl-carbamic acid tert-butyl ester as a white solid(0.42 g, 51%): ¹H NMR (300 MHz, MeOD) δ 7.55 (s, 1H), 7.32-7.27 (m, 2H),7.21-7.19 (m, 1H), 4.54 (s, 2H), 4.21 (s, 2H), 1.28 (s, 9H).

Step 6. Preparation of1{3-[3-Bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamicacid tert-butyl ester

To a solution of 3-bromo-4-(4-fluorobenzyloxy)pyridine-2(1H)-one (fromStep 3, synthesis EXAMPLE 59) (0.2 g, 0.67 mmol) in DMF (11 mL) wasadded K₂CO₃ (0.26 g, 1.3 mmol) and 3-(bromomethyl)benzylcarbamic acidtert-butyl ester (0.23 g, 0.80 mmol), and the reaction mixture wasstirred at 80° C. for 3 hours. The reaction mixture was cooled to roomtemperature, and concentrated under reduced pressure. The residue wasdiluted with a 50% aqueous solution of brine (24 mL), and extracted withCHCl₃ (4×50 mL). The combined organics was washed water and then brine,dried (MgSO₄), filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica, 3:7 EtOAc/hexanes)and recrystallization from MeOH afforded{3-[3-bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamicacid tert-butyl ester as an off-white solid (0.07 g, 20%): mp 136-138°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.37 (m, 2H), 7.30-7.20 (m, 5H), 7.08(t, J=9 Hz, 2H), 6.04 (d, J=9 Hz, 1H), 5.16 (s, 2H), 5.14 (s, 2H), 4.28(d, J=6 Hz, 1H), 1.44 (s, 9H). ESHRMS m/z 517.1124 (M+H C₂₅H₂₇BrFN₂O₄requires 517.1133)

Example 71

1-(3-Aminomethylbenzyl)-3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-one

To an ice-cold solution of1-[3-{N-tert-Butoxycarbonyl}aminomethylbenzyl]-3-bromo-4-(4-fluorobenzyloxy)pyridine-2(1H)-one(Example 69) (0.05 g, 0.1 mmol) in CH₂Cl₂ (2 mL) was added TFA (2 mL),and the reaction mixture was stirred for 1 h. The solvent was removedunder reduced pressure to provide1-(3-aminomethylbenzyl)-3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-oneas a tan solid (0.049 g, 100%), as the TFA salt: mp 127-139° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 8.13 (br s, 2H), 7.94 (d, J=6 Hz, 1H), 7.52 7.47(m, 2H), 7.44-7.37 (m, 2H), 7.27 (t, J=8 Hz, 3H), 6.53 (d, J=8 Hz, 1H),5.30 (s, 2H), 5.14 (s, 2H), 4.01 (d, J=6 Hz, 2H), 3.39 (br s, 2H); Anal.Calcd for C₂₀H₁₇BrF₂N₂O₂.1.125 TFA: C, 48.99; H, 3.53; N, 5.13. Found:C, 48.80; H, 3.43; N, 4.75. ESHRMS m/z 417.0608 (M+H C₂₀H₁₉BrFN₂O₂requires 417.0609).

Example 72

Methyl2-[3-Bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 59 (0.36 g, 48%): mp 161-165° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.98 (d, J=6 Hz, 1H), 7.51-7.26 (m, 6H), 7.11-7.05 (m, 2H),6.05 (d, J=8 Hz, 1H), 5.60 (s, 2H), 5.18 (s, 2H), 3.93 (s, 3H). ESHRMSm/z 446.0430 (M+H C₂₁H₁₈BrFNO₄ requires 418.0398)

Example 73

3-Bromo-4-(4-fluorobenzyloxy)-1-(2-hydroxymethylbenzyl)-1H-pyridin-2-one

To an ice-cold solution of3-bromo-4-(4-fluorobenzyloxy)-1-(2-hydroxymethylbenzyl)-1H-pyridin-2-one(Example 72) (0.25 g, 0.56 mmol) in THF (1 mL) was added LiBH₄ (2.0 Msolution in THF, 0.56 mmol), and the reaction mixture was stirred at 40°C. for 6 hours. The reaction mixture was cooled to room temperature, thesolvent was removed under reduced pressure, and the residue wasdissolved in EtOAc. The organic solution was washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure. ¹H NMR (300MHz, DMSO-d₆) δ 7.82 (d, J=8 Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J=7Hz, 1H), 7.29-7.21 (m, 4H), 6.81 (d, J=7 Hz, 1H), 6.53 (d, J=8 Hz, 1H),5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, J=7 Hz, 2H). ESHRMS m/z418.0437 (M+H C₂₀H₁₈BrFNO₃ requires 418.0449)

Example 74

3-Bromo-4-(2,4-difluorobenzyloxy)-1-[(4-dimethylaminomethyl)benzyl]-1H-pyridin-2-oneStep 1. Preparation of 4-(2,4-Difluorobenzyloxy)pyridine-1-oxide

To an ice-cold solution of sodium hydride (1.2 g of a 60% dispersion inmineral oil, 51 mmol) in DMF (43 mL) was added 2,4-difluorobenzylalcohol (5.7 mL, 51 mmol). The reaction mixture was warmed to roomtemperature, 4-chloropyridine-1-oxide¹ (5.5 g, 43 mmol) was added, andthe reaction mixture was stirred for 6 h. The reaction mixture wasdiluted with a 50% aqueous solution of brine, and extracted with CHCl₃(7×50 mL). The combined organics were dried (MgSO₄), filtered, and thesolvent was removed under reduced pressure. Trituration with Et₂Oafforded 4-(2,4-difluorobenzyloxy)pyridine-1-oxide as an off-white solid(9.1 g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 8.16-8.08 (m, 1H), 7.47-7.36 (m,1H), 6.97-6.81 (m, 1H), 5.09 (d, J=8 Hz, 1H).

Step 2. Preparation of 4-(2,4-Difluorobenzyloxy)-1H-pyridin-2-one

A solution of 4-(2,4-difluorobenzyloxy)pyridine-1-oxide (13.4 g, 57mmol) in acetic anhydride (30 mL) was stirred at reflux for 4 h. Thesolvent was removed under reduced pressure, the residue was diluted with1:1 MeOH/water (60 mL), and the mixture was stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure. Purification byflash column chromatography (silica, eluent methylene chloride to 9:1methylene chloride/methanol) provided4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a light brown solid (4.2g, 31%): ¹H NMR (300 MHz, CDCl₃) δ 7.43 (q, J=8 Hz, 1H), 7.23 (d, J=7Hz, 1H), 6.91-6.87 (m, 2H), 6.02 (dd, J=8, 2 Hz, 1H), 5.97 (d, J=2 Hz,1H), 5.03 (s, 2H).

Step 3. Preparation of3-Bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one(0.75 g, 3.1 mmol) in AcOH (12 mL) was added a solution of bromine (0.2mL, 3.5 mmol) in AcOH (6 mL), and the reaction mixture was stirred 10min. The solvent was removed under reduced pressure to afford3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a white solid (1.0g, 100%): ESI MS m/z 299 [M+H]⁺.

Step 4. Preparation of3-Bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one(0.60 g, 2.5 mmol) in DMF (40 mL) was added K₂CO₃ (0.70 g, 5.1 mmol) andα,α′-dichloro-p-xylene (0.53 g, 3.0 mmol), and the reaction mixture wasstirred at 110° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with brine, and extracted with CHCl₃ (4×100 mL).The combined organics were washed water and then brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure to afford3-bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneas an off-white solid (0.49 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ 7.54 (appq, J=8 Hz, 1H), 7.38-7.28 (m, 5H), 6.94 (td, J=8, 2 Hz, 1H), 6.85 (td,J=8, 2 Hz, 1H), 6.10 (d, J=9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.56(s, 2H).

Step 5. Preparation of3-Bromo-4-(2,4-difluorobenzyloxy)-1-[(4-dimethylaminomethyl)benzyl]-1H-pyridin-2-one

To a sealed tube containing3-bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one(0.49 g, 1.1 mmol) was added a solution of dimethylamine (5.5 mL of a2.0 M solution in THF, 11 mmol), and the reaction mixture was stirredfor 15 h. The solvent was removed under reduced pressure. Purificationby flash column chromatography (silica, eluent methylene chloride to92:7.2:0.8 methylene chloride/methanol/ammonia) provided3-bromo-4-(2,4-difluorobenzyloxy)-1-(4-dimethylaminomethylbenzyl)-1H-pyridin-2-oneas a light yellow solid (0.23 g, 46%): mp 111-113° C.; ¹H NMR (500 MHz,CDCl₃) δ 7.50-7.49 (m, 1H), 7.26-7.22 (m, 5H), 6.90-6.88 (m, 1H),6.82-6.78 (m, 1H), 6.04 (d, J=6 Hz, 1H), 5.16 (s, 2H), 5.11 (s, 2H),3.37 (s, 2H), 2.19 (s, 6H). ESHRMS m/z 463.0782 (M+H C₂₂H₂₂BrF₂N₂O₂requires 463.0827)

Example 75

3-Bromo-4-(2,4-difluorobenzyloxy)-1-[3-(isopropylaminomethyl)benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.06 g, 35%): mp 109-110° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.54 (d, J=6 Hz, 1H), 7.33-7.20 (m, 5H), 6.94 6.81 (m, 2H),6.10 (d, J=6 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 3.77 (s, 2H), 2.88 (t,J=6 Hz, 1H), 1.13 (d, J=6 Hz, 6H). ESHRMS m/z 477.0955 (M+HC₂₃H₂₄BrF₂N₂O₂ requires 477.0984)

Example 76

3-Bromo-4-(2,4-difluorobenzyloxy)-1-[(3-dimethylaminomethyl)benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.06 g, 25%): mp 103-107° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.52 (d, J=8 Hz, 1H), 7.32-7.24 (m, 5H), 6.94 (td, J=9, 3 Hz,1H), 6.84 (td, J=9, 3 Hz, 1H), 6.08 (d, J=8 Hz, 1H), 5.20 (s, 2H), 5.16(s, 2H), 3.44 (s, 2H), 2.24 (s, 6H). ESHRMS m/z 463.0801 (M+HC₂₂H₂₂BrF₂N₂O₂ requires 463.0827).

Example 77

3-Bromo-4-(2,4-difluorobenzyloxy)-1-[(3-methylaminomethyl)benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.05 g, 16%): mp 107-111° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.55 (d, J=6 Hz, 1H), 7.31-7.19 (m, 5H), 6.94-6.81 (m, 2H),6.09 (d, J=6 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 3.73 (s, 2H), 2.45 (s,1H). ESHRMS m/z 449.0652 (M+H C₂₁H₂₀BrF₂N₂O₂ requires 449.0671)

Example 78

{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamicacid tert-butyl ester

The title compound was prepared essentially according to the proceduredescribed in Example 70. mp 80-84° C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.60-7.50 (m, 1H), 7.33-7.21 (m, 5H), 6.97-6.81 (m, 2H), 6.10 (dd, J=8,2 Hz, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 4.87 (br s, 2H), 4.30 (s, 2H)1.45 (s, 9H). ESHRMS m/z 535.1019 (M+H C₂₅H₂₆BrF₂N₂O₄ requires 535.1039)

Example 79

1-[(3-Aminomethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneStep 1. Preparation of1-[(3-Aminomethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To an ice-cold solution of{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamicacid tert-butyl ester (Example 78) (0.05 g, 0.1 mmol) in CH₂Cl₂ (2 mL)was added TFA (2 mL), and the reaction mixture was stirred for 1 hour.The solvent was removed under reduced pressure to provide1-[(3-aminomethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneas a tan solid (0.049 g, 100%), as the TFA salt: mp 80-84° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 8.15 (br s, 3H), 7.97 (d, J=8 Hz, 1H), 7.79-7.60(m, 1H), 7.44-7.30 (m, 4H), 7.20-7.15 (m, 1H), 6.61 (d, J=6 Hz, 1H),5.31 (s, 2H), 5.16 (s, 2H), 4.03 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−74.56 (4.8F), −109.63 (1F), −113.61 (1F). ESHRMS m/z 435.0540 (M+HC₂₀H₁₈BrF₂N₂O₂ requires 435.0515)

Example 80

3-Chloro-4-(2,4-difluorobenzyloxy)-1-[4-(isopropylaminomethyl)benzyl]-1H-pyridin-2-oneStep 1. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To a solution of 4-[(4-fluorobenzyl)oxy]pyridine-2(1H)-one (from Step 2,Example 74) (1.4 g, 5.9 mmol) in AcOH (25 mL) was addedN-chlorosuccinimide (0.95 g, 7.1 mmol) and the reaction mixture washeated at reflux for 2 h. The solvent was removed under reducedpressure. ¹H NMR (300 MHz, MeOD) δ 7.63-7.55 (m, 1H), 7.45 (d, J=8 Hz,1H), 7.07-7.00 (m, 2H), 6.58 (d, J=8 Hz, 1H), 5.31 (d, J=8 Hz, 1H).

Step 2. Preparation of3-Chloro-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

3-Chloro-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-onewas prepared by procedure similar to the one described for3-bromo-1-(4-chloromethyl-benzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one(Step 3, as white solid (0.24 g, 34%): ¹H NMR (300 MHz, CDCl₃) δ 7.53(app q, J=9 Hz, 1H), 7.34 (app q, J=9 Hz, 1H), 7.23 (d, J=8 Hz, 1H),6.94 (td, J=10, 2 Hz, 1H), 6.85 (td, J=10, 2 Hz, 1H), 6.14 (d, J=8 Hz,1H), 5.20 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H).

Step 3. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-[4-(isopropylamino-methyl)benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.17 g, 69%): mp 146-151° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.52 (app q, J=9 Hz, 1H), 7.35-7.21 (m, 5H), 6.94 (td, J=8, 2Hz, 1H), 6.85 (td, J=8, 2 Hz, 1H), 6.18 (d, J=8 Hz, 1H), 5.22 (s, 2H),5.08 (s, 2H), 3.81 (s, 2H), 2.98 (br s, 1H), 1.20 (s, 6H). ESHRMS m/z433.1481 (M+H C₂₃H₂₄ClF₂N₂O₂ requires 433.1489)

Example 81

3-Chloro-4-(2,4-difluorobenzyloxy)-1-[(3-methanesulfonyl)benzyl]-1H-pyridin-2-oneStep 1. Preparation of (3-Methanesulfonyl)phenyl methanol

To an ice-cold solution of 3-(methylsulfonyl)benzoic acid (1.4 g, 7.1mmol) in 2:1 Et₂O/THF (60 mL) was added LiAlH₄ (8.5 mL of 1.0 M solutionin THF, 8.5 mmol), and the reaction mixture was heated at reflux for 1h. The reaction mixture was cooled to 0° C., and the reaction wasquenched with water (15 mL) and 15% NaOH in water (35 mL). The reactionmixture was filtered, concentrated under reduced pressure, and theresidue was dissolved in EtOAc. The organic solution was washed withwater and then brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. Purification by flash column chromatography (silica,eluent 1:2 to 3:1 EtOAc/hexanes) provided (3-methanesulfonyl)phenylmethanol as a clear oil (0.56 g, 42%): ¹H NMR (300 MHz, CDCl₃) δ 7.93(s, 1H), 7.83 (d, J=7 Hz, 1H), 7.64 (d, J=7 Hz, 1H), 7.53 (t, J=7 Hz,1H), 4.78 (d, J=6 Hz, 2H), 3.05 (s, 3H), 2.61 (br s, 1H).

Step 2. Preparation of 1-Chloromethyl-3-methanesulfonylbenzene

A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1 mmol) inthionyl chloride (3 mL) was heated at 80° C. for 3 h. The reactionmixture was cooled to room temperature, and the solvent was removedunder reduced pressure to provide1-chloromethyl-3-methanesulfonylbenzene as a yellow oil (0.23 g, 95%):¹H NMR (300 MHz, CDCl₃) δ 7.98 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.70 (d,J=8 Hz, 1H), 7.59 (t, J=8 Hz, 1H), 4.65 (s, 2H), 3.08 (s, 3H).

Step 3. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-[(3-methanesulfonyl)-benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 80 (0.14 g, 78%): mp 155-157° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8 Hz, 1H), 7.83 (m, 1H), 7.67 (d, J=8 Hz, 1H),7.58-7.48 (m, 2H), 7.31 (d, J=8 Hz, 1H), 6.95-6.83 (m, 2H), 6.22 (d, J=8Hz, 1H), 5.22 (s, 4H), 3.08 (s, 3H). ESHRMS m/z 440.0525 (M+HC₂₀H₁₇ClF₂NO₄S requires 440.0529)

Example 82

3-Chloro-4-(2,4-difluorobenzyloxy)-1-[(4methanesulfonyl)benzyl]-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 81-(0.08 g, 73%): mp 223-225° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.91 (d, J=8 Hz, 2H), 7.53-7.47 (m, 3H), 7.30-7.26 (m, 1H),6.94-6.86 (m, 2H), 6.22 (d, J=8 Hz, 1H), 5.23 (s, 4H), 3.03 (s, 3H).ESHRMS m/z 440.0512 (M+H C₂₀H₁₇ClF₂NO₄S requires 440.0529)

Example 83

4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamideStep 1. Preparation of Methyl4-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate

Methyl4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoatewas prepared by a procedure similar to the one described for Example81-(0.14 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ 8.01 (dd, J=8, 2 Hz, 1H),7.52 (app q, J=8 Hz, 1H), 7.36 (d, J=9 Hz, 2H), 7.26-7.22 (m, 2H), 6.94(td, J=8, 2 Hz, 1H), 6.85 (td, J=8, 2 Hz, 1H), 6.16 (d, J=9 Hz, 1H),5.21 (s, 4H), 3.92 (s, 3H).

Step 2. Preparation of4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamide

A sealed tube containing a solution of4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoicacid methyl ester (0.25 g, 0.60 mmol) and NH₃ (20 mL of a 7 N solutionin MeOH, 140 mmol) was heated at 75° C. for 16 h. The reaction mixturewas cooled to room temperature and the solvent was removed under reducedpressure. Trituration with Et₂O/MeOH afforded4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamideas a white solid (0.14 g, 60%): mp 235-238° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 7.93 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 7.60 (app q, J=8Hz, 1H), 7.35-7.27 (m, 4H), 7.20-7.10 (m, 1H), 6.61 (d, J=8 Hz, 1H),5.28 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 405.0788 (M+H C₂₀H₁₆ClF₂N₂O₃requires 405.0812)

Example 84

3-Chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-oneStep 1. Preparation of Isoquinolin-5-ylmethanol

To an ice-cold solution of isoquinoline-5-carbaldehyde² (0.68 g, 4.3mmol) in MeOH (15 mL) was added NaBH₄ (0.17 g, 4.6 mmol), and thereaction mixture was stirred for 15 min. The reaction was quenched withbrine, the solvent was removed under reduced pressure, and the residuewas dissolved in EtOAc. The organic solution was washed with water andthen brine, dried (Na₂SO₄), filtered, and concentrated under reducedpressure to afford isoquinolin-5-ylmethanol as a brown solid (0.63 g,93%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.87 (s, 1H), 8.82 (d, J=6 Hz, 1H),8.57 (d, J=6 Hz, 1H), 8.47 (d, J=9 Hz, 1H), 8.30 (d, J=6 Hz, 1H), 7.95(t, J=9 Hz, 1H), 5.34 (s, 2H).

Step 2. Preparation of 5-Bromomethylisoquinoline

To a solution of isoquinolin-5-ylmethanol (0.63 g, 3.9 mmol) in AcOH(3.3 mL) was added HBr (6.6 mL, a 30% w/w solution in AcOH, 24 mmol),and the reaction mixture was stirred at 75° C. for 45 min. The reactionmixture was cooled to room temperature, and the precipitate wascollected to provide the 5-bromomethylisoquinoline hydrobromide acidsalt as a brown solid (1.1 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s,1H), 8.58 (d, J=6 Hz, 1H), 7.95-7.89 (m, 2H), 7.76 (d, J=9 Hz, 1H), 7.59(dd, J=9, 6 Hz, 1H), 5.16 (s, 2H).

Step 3. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 81, as the TFA salt (0.13 g, 33%): mp 235-238° C.;¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.66 (d, J=6 Hz, 1H), 8.29 (d,J=6 Hz, 1H), 8.22 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.77 (t, J=8Hz, 1H), 7.65-7.63 (m, 1H), 7.53 (d, J=7 Hz, 1H), 7.35-7.25 (m, 1H),7.20-7.10 (m, 1H), 6.68 (d, J=8 Hz, 1H), 5.67 (s, 2H), 5.32 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −74.79 (3F), −109.43 (1F), −113.62 (1F). ESHRMSm/z 413.0868 (M+H C₂₂H₁₆ClF₂N₂O₃ requires 413.0863)

Example 85

3-Chloro-4-(2,4-difluorobenzyloxy)-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-1H-pyridin-2-oneStep 1. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-(1,2,3,4-tetrahydro-isoquinolin-5-ylmethyl)-1H-pyridin-2-one

To a solution of3-chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-one(Example 84) (0.14 g, 0.34 mmol) in AcOH (1.3 mL) was added NaCNBH₃(0.09 g, 1.4 mmol), and the reaction mixture was stirred for 2 h. Thereaction mixture was cooled to 0° C., and diluted with water (10 mL) and40% aqueous NaOH (10 mL), and the aqueous layer was washed with EtOAc(3×50 mL). The combined organics were washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Purification by flashcolumn chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2CH₂Cl₂/MeOH/NH₃) provided3-chloro-4-(2,4-difluoro-benzyloxy)-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-1H-pyridin-2-oneas a white solid (0.13 g, 92%): mp 180-184° C.; ¹H NMR (300 MHz, MeOD) δ7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90-6.80 (m, 1H), 6.60 (d, J=8Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, J=6 Hz, 2H),2.82 (t, J=6 Hz, 2H). ESHRMS m/z 417.1173 (M+H C₂₂H₂₀ClF₂N₂O₂ requires417.1176)

Example 86

3-Chloro-4-(2,4-difluorobenzyloxy)-1-(1Hindol-5-ylmethyl)-1H-pyridin-2-one Step 1. Preparation of5-(Carboxymethyl)-indole-1-carbamic acid tert-butyl ester

To a solution of methyl indole-5-carboxylate (6.9 g, 39 mmol) and Et₃N(6.0 mL, 43 mmol) in CH₂Cl₂ (150 mL) was added di-tert-butyl dicarbonate(19 g, 86 mmol), and the reaction mixture was stirred for 14 h. Thereaction mixture was diluted with CH₂Cl₂, washed with water and thenbrine, dried (Na₂SO₄), filtered, and the solvent was removed underreduced pressure. Purification by flash column chromatography (silica,3:7 EtOAc/hexanes) provided 5-(carboxymethyl)-indole-1-carbamic acidtert-butyl ester as a light yellow oil (11 g, 100%): ¹H NMR (300 MHz,CDCl₃) δ 8.29 (s, 1H), 8.15 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 7.78(d, J=3 Hz, 1H), 6.85 (d, J=3 Hz, 1H), 3.91 (s, 3H), 1.68 (s, 9H).

Step 2. Preparation of 5-Hydroxymethylindole-1-carbamic acid tert-butylester

To a −78° C. solution of 5-(carboxymethyl)-indole-1-carbamic acidtert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) was added DIBAL (127mL of a 1 M solution in THF, 127 mmol), and the reaction mixture wasstirred for 2.5 h. The reaction was quenched with 1:1 1 N HCl/MeOH (100mL), the reaction mixture was warmed to room temperature, diluted withCH₂Cl₂ (100 mL), and separated. The organic solution was washed withsaturated Rochelle salt, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. Purification by flash column chromatography(silica, 1:1 EtOAc/hexanes) provided 5-hydroxymethylindole-1-carbamicacid tert-butyl ester as a yellow oil (6.5 g, 68%): ¹H NMR (300 MHz,CDCl₃) δ 8.07 (d, J=9 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.54 (s, 1H), 7.28(d, J=9 Hz, 1H), 6.58 (d, J=6 Hz, 1H), 4.73 (s, 2H), 1.97 (s, 9H).

Step 3. Preparation of 5-Bromomethylindole-1-carbamic acid tert-butylester

To an ice-cold solution of 5-hydroxymethylindole-1-carbamic acidtert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et₂O/CH₂Cl₂ (4 mL) was addedPBr₃ (0.2 mL, 2.2 mmol), and the reaction mixture was stirred for 40min. The reaction mixture was diluted with CH₂Cl₂, washed a saturatedsolution of NaHCO₃ (3×10 mL), dried (Na₂SO₄), filtered, and the solventwas removed under reduced pressure to provide5-bromomethyl-indole-1-carbamic acid tert-butyl ester as a yellow solid(0.59 g, 93%). ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, J=9 Hz, 1H), 7.68-7.62(m, 2H), 7.33 (d, J=9 Hz, 1H), 6.60 (s, 1H), 4.68 (s, 2H), 1.67 (s, 9H).

Step 4. Preparation of5-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester

5-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester was prepared by a procedure similar to the onedescribed for Example 81 as an off-white solid (0.54 g, 67%): ¹H NMR(300 MHz, CDCl₃) δ 8.10 (d, J=8 Hz, 1H), 7.60 (d, J=3 Hz, 2H), 7.52 (m,1H), 7.26 (m, 1H), 6.94 (td, J=9, 2 Hz, 1H), 6.84 (td, J=9, 2 Hz, 1H)6.53 (d, J=2 Hz, 1H), 6.08 (d, J=8 Hz, 1H), 5.25 (s, 2H), 5.18 (s, 2H),1.66 (s, 9H).

Step 5. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one

A flask containing5-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester (0.48 g, 0.96 mmol) was heated at 150° C. for 4 h.The reaction mixture was cooled to room temperature, and purification bypreparatory HPLC (Phenomenex Luna C18 (2) column, 250×21.20 mm, 10μ

Solvent A: 0.05% TFA in 95:5 H₂O/CH₃CN; Solvent B: 0.05% TFA in 95:5CH₃CN/H₂O

Eluent: 30-95% B over 20 min; flow 20.0 mL/min; UV Detector: 254 nm;Retention Time: 15.6 min) provided3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-oneas an off white solid (0.14 g, 36%): mp 152-153° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 11.11 (br s, 1H), 7.91 (d, J=8 Hz, 1H), 7.61 (app q, J=8 Hz,1H, 7.51 (s, 1H), 7.36-7.33 (m, 3H), 7.16 (td, J=8, 2 Hz, 1H), 7.09 (dd,J=8, 2 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 6.40 (br s, 1H), 5.28 (s, 2H),5.16 (s, 2H). ESHRMS m/z 401.0845 (M+H C₂₁H₁₆ClF₂N₂O₂ requires401.0863).

Example 87

1-(1-Acetyl-1H-indol-5-ylmethyl)-3-chloro-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To a solution of3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one(Step 5, synthesis of Example 86) (0.22 g, 0.57 mmol) in CH₃CN (10 mL)was added acetic anhydride (0.06 mL, 0.58 mmol) and Et₃N (2 mL), and thereaction mixture was stirred at 86° C. for 6 h. The reaction mixture wascooled to room temperature, and partitioned between 1 N HCl and EtOAc.The organic solution was separated, washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. ¹H NMR (300 MHz,MeOD) δ 8.35 (d, J=9 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.70 (d, J=3 Hz,1H), 7.54 (s, 2H), 7.31 (d, J=9 Hz, 1H), 7.01-6.99 (m, 2H), 6.66 (d, J=3Hz, 1H), 6.59 (d, J=9 Hz, 1H), 5.29 (s, 4H), 2.63 (s, 3H). ESHRMS m/z443.0965 (M+H C₂₃H₁₈ClF₂N₂O₃ requires 443.0969).

Example 88

3-Chloro-4-(2,4-difluorobenzyloxy)-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-one

To a solution of3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one(Step 5, synthesis of Example 86) (0.24 g, 0.60 mmol) in AcOH (5 mL) wasadded NaCNBH₃ (0.06 g, 1.0 mmol), and the reaction mixture was stirredfor 1 h. The reaction mixture was partitioned between water and EtOAc,and the precipitate was collected by filtration. Trituration with CH₂Cl₂afforded3-Chloro-4-(2,4-difluorobenzyl-oxy)-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-oneas a white solid (0.2 g, 81%): mp 137-139° C.; ¹H NMR (300 MHz, CDCl₃) δ7.51 (app q, J=9 Hz, 1H), 7.21 (d, J=6 Hz, 1H), 7.11 (s, 1H), 6.99-6.80(m, 3H), 6.57 (d, J=9 Hz, 1H), 6.08 (d, J=9 Hz, 1H), 5.18 (s, 2H), 5.02(s, 2H), 3.83 (br s, 1H), 3.55 (t, J=9 Hz, 2H), 2.99 (t, J=9 Hz, 2H).ESHRMS m/z 403.1022 (M+H C₂₁H₁₈ClF₂N₂O₂ requires 403.1019).

The following example compounds were prepared by procedures similar tothat described for Example 74. The yields and the analytical data of thetitle compounds are reported below.

Examples 89-101

The compounds of Examples 89-101 are prepared essentially according tothe procedures set forth above for Example 74. The yield (Y), molecularformula (MF) and analytical data for these compounds are shown below.

Example M + H ESHRMS No. R Y MF Requires m/z Ex. 89 pyridin-3- 25C₁₈H₁₃BrF₂N₂O₂ 407.0202 407.0197 ylmethyl Ex. 90 pyridin-4- 6C₁₈H₁₃BrF₂N₂O₂ 407.0202 407.0189 ylmethyl Ex. 91 pyridin-2- 56C₁₈H₁₃BrF₂N₂O₂ 407.0201 407.0184 ylmethyl Ex. 92 4-tert-butyl) 32C₂₃H₂₂BrF₂NO₂ 462.0875 462.0863 benzyl Ex. 93 3-methoxy- 50C₂₀H₁₆BrF₂NO₃ 436.0354 436.0353 benzyl Ex. 94 Benzo[1,3] 35C₂₀H₁₄BrF₂NO₄ 450.0147 450.0136 dioxol-5- ylmethyl Ex. 95 2-fluoro 42C₁₉H₁₄BrF₃NO₂ 424.0155 424.0143 benzyl

%): mp 179-182° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.53 (m, 3H),7.33-7.26 (m, 1H), 7.14-7.02 (m, 2H), 6.96-6.82 (m, 2H), 6.11 (d, J=9Hz, 1H), 5.20 (s, 2H), 5.18 (s, 2H). ESHRMS m/z (M+H requires).

Example 96

3-Bromo-4-(2,4-difluorobenzyloxy)-1-(2,4-difluorobenzyl)-1H-pyridin-2-oneStep 1. Preparation of4-(2,4-Difluorobenzyloxy)-1-(2,4-difluorobenzyl)-1H-pyridin-2-one

To a solution of 2,4-dihydroxypyridine (0.35 g, 3.2 mmol) in DMF (50 mL)was added K₂CO₃ (2.5 g, 13 mmol) and 2,4-difluorobenzyl bromide (1.0 mL,7.6 mmol), and the reaction mixture was stirred at 110° C. for 4 h. Thereaction mixture was cooled to room temperature, diluted with brine, andextracted with CHCl₃ (4×100 mL). The combined organics were washed withwater and then brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. ¹H NMR (300 MHz, CDCl₃) δ 7.54 (app q, J=8 Hz, 1H),7.38-7.28 (m, 5H), 6.94 (td, J=8, 2 Hz, 1H), 6.85 (td, J=8, 2 Hz, 1H),6.10 (d, J=9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H).

Step 2. Preparation of3-Bromo-4-(2,4-difluorobenzyloxy)-1-(2,4-fluorobenzyl)-1H-pyridin-2-one

To an ice-cold solution of4-(2,4-difluorobenzyloxy)-1-(2,4-difluorobenzyl)-1H-pyridin-2-one (0.72g, 2.0 mmol) in AcOH (4.0 mL) was added a solution of bromine (0.11 mL,2.2 mmol) in AcOH (7.2 mL), and the reaction mixture was stirred for 40min. The solvent was removed under reduced pressure. ¹H NMR (300 MHz,CDCl₃) δ 7.63-7.45 (m, 2H), 7.42 (d, J=6 Hz, 1H), 6.93-6.77 (m, 4H),6.12 (d, J=6 Hz, 1H), 5.20 (s, 2H), 5.12 (s, 2H). ERMS m/z M+H 442.

Example 97

{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2oxo-2H-pyridin-1-ylmethyl]-phenyl}acetonitrile Step 1. Preparation ofMethyl 3-cyanomethylbenzoate

To an ice-cold solution of methyl 3-bromomethylbenzoate (9.1 g, 40 mmol)in CH₃CN (108 mL) was added tetrabutylammonium fluoride (17.3 mL, 60mmol) and trimethylsilylcyanide (8.0 mL, 60 mmol), and the reactionmixture was heated at reflux for 20 h. The reaction mixture was cooledto room temperature, and the solvent was removed under reduced pressure.Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes)provided methyl 3-cyanomethylbenzoate as a clear oil (3.0 g, 43%): ¹HNMR (300 MHz, DMSO-d₆) δ 7.97 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.64 (d,J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 4.16 (s, 2H), 3.87 (s, 3H).

Step 2. Preparation of (3-Hydroxymethylphenyl)acetonitrile

To an ice-cold solution of methyl 3-cyanomethylbenzoate (2.8 g, 18 mmol)in THF (23 mL) was added LiBH₄ (8.8 mL of a 2 M solution in THF, 18mmol), and the reaction mixture was heated at reflux for 4 h. Thereaction mixture was cooled to room temperature, the reaction wasquenched with 1:1 water/1 N HCl, and the aqueous layer was washed withEtOAc (3×150 mL). The combined organics were washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure.

Purification by flash column chromatography (silica, 2:1 EtOAc/hexanes)provided (3-hydroxymethylphenyl)acetonitrile as a clear oil (0.97 g,41%): ¹H NMR (300 MHz, MeOD) δ 8.15-8.08 (m, 1H), 7.47-7.34 (m, 1H),7.27 (s, 1H), 6.97-6.82 (m, 1H), 4.87 (s, 2H), 3.91 (s, 2H)

Step 3. Preparation of (3-Bromomethylphenyl)acetonitrile

To an ice-cold solution of (3-hydroxymethylphenyl)acetonitrile (0.97 g,7.3 mmol) in THF (35 mL) was added CBr₄ (2.5 g, 7.7 mmol) and Ph₃P (2.0g, 7.7 mmol), and the reaction mixture was stirred for 3 h. The reactionmixture was filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica, eluent 1:9 to 1:4EtOAc/hexanes) provided (3-bromomethylphenyl)acetonitrile as a clear oil(0.89 g, 58%): ¹H NMR (300 MHz, MeOD) δ 7.47-7.29 (m, 1H), 7.27 (s, 1H),6.97 6.82 (m, 1H), 4.87 (s, 2H), 3.91 (s, 2H).

Step 4. Preparation of{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}acetonitrile

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.07 g, 10%): mp 120-121° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.60-7.50 (m, 1H), 7.37-7.27 (m, 5H), 6.96 (td, J=9, 3 Hz, 1H),6.82 (td, J=9, 3 Hz, 1H), 6.13 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.16 (s,2H). ESHRMS m/z 445.0381 (M+H C₂₁H₁₆BrF₂N₂O₂ requires 445.0358).

Example 98

2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzonitrile

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.13 g, 47%): mp 194-197° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, J=9 Hz, 1H), 7.69-7.49 (m, 4H), 7.42 (t, J=8 Hz, 1H),6.96-6.73 (m, 2H), 6.18 (d, J=8 Hz, H), 6.17 (s, 2H), 5.30 (s, 2H).ESHRMS m/z 431.0210 (M+H C₂₀H₁₄BrF₂N₂O₂ requires 431.0201.

Example 99

1-[(2-Aminomethyl)benzyl)]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

To a solution of2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzonitrile(0.11 g, 0.25 mmol) in THF (3 mL) was added BH₃.DMS (0.25 mL of a 2.0 Msolution in THF, 0.5 mmol), and the reaction mixture was stirred at 70°C. for 1 h. The reaction mixture was cooled to 0° C., and the reactionwas quenched with MeOH. The solvent was removed under reduced pressure,and the residue was partitioned between 2N NaOH and EtOAc. The organicsolution was washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure. Purification by flash columnchromatography (silica, eluent methylene chloride to 90:9:1 methylenechloride/methanol/ammonia) provided1-[(2-aminomethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneas a white solid (0.15 g, 48%): ¹H NMR (300 MHz, CDCl₃) δ 7.55 (app q,J=8 Hz, 1H), 7.40-7.26 (m, 4H), 7.14 (d, J=8 Hz, 1H), 6.94 (td, J=8, 2Hz, 1H), 6.85 (td, J=8, 2 Hz, 1H), 6.08 (d, J=8 Hz, 1H), 5.31 (s, 2H),5.21 (s, 2H) 4.03 (s, 2H). ESHRMS m/z 435 0517 (M+H C₂₀H₁₈BrF₂N₂O₂requires 435.0514).

Example 100

Methyl3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.05 g, 11%): mp 115-117° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.15-7 95 (m, 2H), 7.65-7.50 (m, 2H), 7.45-7.40 (m, 1H), 7.32(d, J=6 Hz, 1H), 7.00-6.80 (m, 2H), 6.12 (d, J=9 Hz, 1H), 5.21 (s, 2H),5.20 (s, 2H), 3.92 (s, 3H). ESHRMS m/z 464.0292 (M+H C₂₁H₁₇BrF₂NO₄requires 464.0303).

Example 101

Methyl4-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-benzoate

The title compound was prepared by a procedure similar to the onedescribed for Example 74 (0.17 g, 46%): mp 136-139° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.01 (d, J=8 Hz, 2H), 7.60-7.51 (m, 1H), 7.37 (d, J=8 Hz, 2H),7.29-7.26 (m, 1H), 6.93 (td, J=9, 2 Hz, 1H), 6.84 (td, J=9, 2 Hz, 1H),6.13 (d, J=8 Hz, 1H), 5.23 (s, 4H), 3.91 (s, 3H). ESHRMS m/z 464.0306(M+H C₂₁H₁₇BrF₂NO₂ requires 464.0304).

Example 102

3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamide

A sealed tube containing a solution of methyl3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate(0.1 g, 0.21 mmol) and NH₃ (3 mL of a 7 N solution in MeOH, 21 mmol) washeated at 75° C. for 16 h. The reaction mixture was cooled to roomtemperature and the solvent was removed under reduced pressure.Trituration with Et₂O/MeOH afforded a white solid (0.06 g, 64%): mp198-201° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.02-8.00 (m, 2H), 7.85-7.75(m, 2H), 7.70-7.60 (m, 1H), 7.45-7.30 (m, 4H), 7.17 (t, J=3 Hz, 1H),6.60 (d, J=9 Hz, 1H), 5.32 (s, 2H), 5.18 (s, 2H). ESHRMS m/z 449.0295(M+H C₂₀H₁₆BrF₂N₂O₃ requires 449.0307).

Example 103

4-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamide

The title compound was prepared by a procedure similar to the onedescribed for Example 102 from Example 101-(0.04 g, 12%): mp 235-238°C.; ¹H NMR (300 MHz, DMSO d₆) δ 8.00 (d, J=8 Hz, 1H), 7.94 (br s, 1H),7.78 (d, J=8 Hz, 1H), 7.64 (app q, J=8 Hz, 1H), 7.38-7.30 (m, 4H), 7.17(td, J=6, 2 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 5.27 (s, 2H), 5.14 (s, 2H).ESHRMS m/z 449.0291 (M+H C₂₀H₁₆BrF₂N₂O₃ requires 449.0307).

Example 104

1-(3-Aminomethyl-2-fluorobenzyl)-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneStep 1. Preparation of 3-Bromo-1-(3-bromomethyl2-fluorobenzyl)-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one

To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one(from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was addedK₂CO₃ (0.26 g, 1.9 mmol) and 2,6-bis(bromomethyl)fluorobenzene (1.6 g,5.7 mmol), and the reaction mixture was stirred at 110° C. for 3 h. Thereaction mixture was cooled to room temperature, and the solvent wasremoved under reduced pressure. The residue was diluted with a 50%aqueous solution of brine, and the aqueous layer was extracted withEtOAc (3×50 mL). The combined organics were washed with water, dried(Na₂SO₄), filtered, and the solvent was removed under reduced pressure.Purification by flash column chromatography (silica, eluent 99:1 to 95:5methylene chloride/methanol) afforded3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneas an off-white solid (0.24 g, 49%): ¹H NMR (300 MHz, CDCl₃) δ 7.55-7.40(m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14(d, J=6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H).

Step 2. Preparation of1-(3-Aminomethyl-2-fluorobenzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one

A sealed tube containing a solution of3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one(0.24 g, 0.45 mmol) and NH₃ (24 mL of a 7 N solution in MeOH, 168 mmol)was heated at 80° C. for 1 h. The reaction mixture was cooled to roomtemperature and the solvent was removed under reduced pressure.Purification by flash column chromatography (silica, eluent 99.5:0.5 to96:4 methylene chloride/methanol) afforded a white solid (0.12 g, 60%):mp 160-163° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.45 (m, 1H), 7.44-7.35(m, 2H), 7.34-7.26 (m, 1H), 7.15-7.05 (m, 1H), 6.95-6.80 (m, 2H), 6.11(d, J=9 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H). ESHRMS m/z453.0442 (M+H C₂₀H₁₇BrF₃N₂O₂ requires 453.0420).

Example 105

Methyl3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluoro-benzoateStep 1. Preparation of Methyl 2-fluoro-3-methylbenzoate

To a solution of 2-fluoro-3-methyl benzoic acid (3.57 g, 23 mmol) inMeOH (40 mL) was added concentrated sulfuric acid (2.3 mL), and thereaction mixture was heated at reflux for 12 h. The reaction mixture wascooled, the solvent was removed under reduced pressure, and the residuewas dissolved in EtOAc. The organic solution was washed with a saturatedsolution of NaHCO₃ and then brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford methyl 2fluoro-3-methylbenzoate as a yellow oil (3.2 g, 82%): ¹H NMR (300 MHz,CDCl₃) δ 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J=8 Hz, 1H),3.98 (s, 3H), 2.31 (d, J=3 Hz, 3H).

Step 2. Preparation of Methyl 3-bromomethyl-2-fluorobenzoate

To a mixture of methyl 2-fluoro-3-methylbenzoate (1.5 g, 8.9 mmol) andN-bromosuccinimide (1.67 g, 9.4 mmol) was added carbon tetrachloride (24mL) and benzoyl peroxide (5 mg), and the mixture was heated at refluxfor 16 h. The reaction mixture was cooled, filtered, and concentratedunder reduced pressure. Purification by flash column chromatography(silica, eluent 5:95 to 60:40 EtOAc/hexanes) afforded methyl3-bromomethyl-2-fluorobenzoate as a light yellow solid (0.91 g, 41%): ¹HNMR (300 MHz, CDCl₃) δ 7.93-7.88 (m, 1H), 7.61-7.56 (m, 1H), 7.20 (t,J=8 Hz, 1H), 4.53 (d, J=3 Hz, 2H), 3.94 (s, 3H).

Step 3. Preparation of Methyl3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluorobenzoate

Methyl3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluorobenzoatewas prepared by a procedure similar to the one described for Example81-(0.33 g, 69%): mp 171-174° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.84(m, 2H), 7.60-7.45 (m, 2H), 7.25-7.15 (m, 1H), 7.00-6.80 (m, 2H), 6.17(d, J=6.0 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H). ESHRMS m/z438.0747 (M+H C₂₁H₁₆ClF₃NO₄ requires 438.0714).

Example 106

3-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-2-fluorobenzamide

The title compound was prepared by a procedure similar to the onedescribed for Example 99 (0.15 g, 62%): mp 252-254° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=8 Hz, 1H), 7.92 (br s, 1H), 7.79-7.65 (m, 3H),7.49-7.48 (m, 1H), 7.37-7.31 (m, 3H), 6.80 (d, J=8 Hz, 1H), 5.46 (s,2H), 5.33 (s, 2H). ESHRMS m/z 423.0710 (M+H C₂₀H₁₅ClF₃N₂O₃ requires423.0718).

Example 107

3-Bromo-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-oneStep 1. Preparation of 4-Benzyloxy-1-(3-fluorobenzyl)-1H-pyridin-2-one

To a solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 5 mmol) and K₂CO₃(2.0 g, 9.9 mmol) in DMF (30 mL) was added 3-fluorobenzyl bromide (1.4g, 7.5 mmol), and the reaction mixture was heated to 110° C. for 3 h.The reaction mixture was cooled to room temperature, and partitionedbetween EtOAc and water. The organic solution was washed with water andthen brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography (silica, eluent97:3 to 93:7 methylene chloride/methanol) afforded4-benzyloxy-1-(3-fluorobenzyl)-1H-pyridin-2-one (1.04 g, 67%): ¹H NMR(300 MHz, CDCl₃) δ 7.45-7.25 (m, 5H), 7.13 (d, J=8 Hz, 1H), 7.10-6.90(m, 3H), 6.10-5.95 (m, 2H), 5.07 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of 1-(3-Fluorobenzyl)-4-hydroxy-1H-pyridin-2-one

To a solution of 4-benzyloxy-1-(3-fluorobenzyl)-1H-pyridin-2-one (1.79g, 5.8 mmol) in EtOH (50 mL) was added 10% Pd/C (0.4 g), and reactionmixture was stirred under a hydrogen atmosphere for 1.5 h. The reactionmixture was filtered through diatomaceous earth and concentrated underreduced pressure to give 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one(0.92 g, 72%): ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=6 Hz, 1H), 7.40-7.30(m, 1H), 7.10-6.95 (m, 3H), 6.07 (dd, J=6, 3 Hz, 1H), 5.85 (d, J=3 Hz,1H), 5.11 (s, 2H).

Step 3. Preparation of3-Bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one

To an ice-cold solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one(0.67 g, 3.1 mmol) in AcOH (5.7 mL) was added a solution of bromine(0.52 g, 3.24 mmol) in AcOH (10.8 mL), and the reaction mixture wasstirred for 5 min. The reaction mixture was warmed to room temperatureand concentrated under reduced pressure to afford3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one as a yellow solid(1.07 g, crude): ¹H NMR (500 MHz, MeOD) δ 7.64 (d, J=8 Hz, 1H),7.35-7.30 (m, 1H), 7.05-6.90 (m, 3H), 6.20 (d, J=8 Hz, 1H), 5.18 (s,2H).

Step 4. Preparation of3-Bromo-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

To a solution of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one(0.20 g, 0.67) and K₂CO₃ (0.27 g, 1.34 mmol) in acetone (10 mL) wasadded 2,4-difluorobenzyl bromide (0.16 g, 0.8 mmol), and the reactionmixture was heated at reflux for 1 h. The reaction mixture was cooled toroom temperature, concentrated under reduced pressure, and the residuewas dissolved in EtOAc. The organic solution was washed with water andthen brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.55 (m, 1H), 7.40-7.25 (m,2H), 7.15-6.80 (m, 5H), 6.14 (d, J=8 Hz, 1H), 5.22 (s, 2H), 5.16 (s,2H). ESHRMS m/z 424.0159 (M+H C₁₉H₁₄BrF₃NO₂ requires 424.0155).

Example 108

3-Bromo-1-(3-fluorobenzyl)-4-(2,3,4-trifluorobenzyloxy)-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for Example 107 (0.09 g, 39%): mp 176-178° C.; ¹H NMR (300MHz, CDCl₃) δ 7.40-7.25 (m, 4H), 7.11-6.98 (m, 4H), 6.11 (d, J=9 Hz,1H), 5.23 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 442.0060 (M+H C₁₉H₁₃BrF₄NO₂requires 442.0061).

Example 109

1-[3-(2-Aminoethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one

The title compound was prepared from compound of Example 97 by aprocedure similar to the one described for Example 99, as the TFA salt(0.13 g, 33%): mp 70-74° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (br s,1H), 6.60-6.50 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.30 7.10 (m, 3H), 7.01(d, J=9 Hz, 1H), 6.94-6.85 (m, 2H), 6.20 (d, J=6 Hz, 1H), 5.20 (s, 2H),5.05 (s, 2H), 3.23 (br s, 2H), 2.97 (t, J=8 Hz, 2H), 2.05 (br s, 2H).ESHRMS m/z 449.0698 (M+H C₂₁H₂₀BrF₂N₂O₂ requires 449.0671).

Example 110

3-Chloro-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-oneStep 1. Preparation of4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

To a solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (fromStep 2 EXAMPLE 107) (0.92 g, 4.2 mmol) and K₂CO₃ (1.2 g, 8.4 mmol) inacetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol),and the reaction mixture was heated at reflux for 3 h. The reactionmixture was cooled room temperature, concentrated under reducedpressure, and the residue was partitioned between water and EtOAc. Theorganic solution was washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification by flash columnchromatography (silica, eluent methylene chloride to 95:5 methylenechloride/methanol) to provide4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one as a whitesolid (1.21 g, 84%): ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.20 (m, 2H), 7.14(d, J=8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J=3 Hz, 1H), 5.95 (dd, J=5,3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

To a solution of4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g,0.4 mmol) in AcOH (3 mL) was added N-chlorosuccinimide (70 mg, 0.5mmol), and the reaction mixture was heated at reflux for 10 min. Thereaction mixture was cooled room temperature and the solvent was removedunder reduced pressure. ¹H NMR (300, MHz, CDCl₃) δ 7.60-7.50 (m, 1H),7.45-7.20 (m, 2H), 7.10-6.80 (m, 5H), 6.16 (d, J=8 Hz, 1H), 5.21 (s,2H), 5.15 (s, 2H). ESHRMS m/z 380.0641 (M+H C₁₉H₁₄ClF₃NO₂ requires480.0660).

Examples 111-123

The following example compounds were prepared by procedures similar tothat described for Example 107. The yields and the analytical data aredescribed below.

Example 111

3-Bromo-4-(3-chlorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 107 (0.12 g, 42w): mp 149-153° C.; ¹H NMR (300MHz, CDCl₃) δ 7.40-7.23 (m, 6H), 7.09 (d, J=8 Hz, 1H), 7.05-6.95 (m,2H), 6.05 (d, J=8 Hz, 1H), 5.19 (s, 2H), 5.14 (s, 2H). ESMS m/z M+H 442.

Example 112

3-Bromo-4-(3,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 107 (0.08 g, 48%): mp 172-174° C.; ¹H NMR (300MHz, CDCl₃) δ 7.40-6.95 (m, 8H), 6.05 (d, J=6 Hz, 1H), 5.16 (s, 4H).ESHRMS m/z 424.0111 (M+H C₁₉H₁₄BrF₃NO₂ requires 424.0155).

Example 113

3-Bromo-1-(3-fluorobenzyl)-4-(4-fluorobenzyloxy)-1H-pyridin-2-one

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 107 (0.07 g, 35%): mp 180-183° C.; ¹H NMR (300MHz, CDCl₃) δ 7.50-7.25 (m, 5H), 7.15-7.00 (m, 4H), 6.07 (d, J=8 Hz,1H), 5.18 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 406.0258 (M+H C₁₉H₁₅BrF₂NO₂requires 406-0249).

Example 114

3-Bromo-1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-1H-pyridin-2-one

To an ice-cold solution of1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-1H-pyridin-2-one (0.14 g, 0.43mmol) in AcOH (2 mL) was added a solution of bromine (72 mg, 0.45 mmol)in AcOH (1 mL), and the reaction mixture was stirred for 5 min. Thereaction mixture was warmed to room temperature and the solvent wasremoved under reduced pressure. ¹H NMR (300 MHz, CDCl₃) δ 7.45-6.95 (m,9H), 6.05 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.14 (s, 2H). ESHRMS m/z406.0254 (M+H C₁₉H₁₅BrF₂NO₂ requires 406.0249).

Examples 115-123

The compounds of Examples 115-123 are prepared essentially according tothe procedures set forth above for Example 107:

Example M + H ESHRMS No. R MF Requires m/z Ex. 115 3-methoxyC₂₀H₁₇BrFNO₃ 418.0449 418.0427 Ex. 116 4-tert-butyl C₂₃H₂₃BrFNO₂444.0969 444.0977 Ex. 117 3-methyl C₂₀H₁₇BrFNO₂ 402.0499 402.0513 Ex.118 4-trifluoromethyl C₂₀H₁₄BrF₄NO₂ 456.0217 456.0210 Ex. 119 4-cyanoC₂₀H₁₄BrFN₂O₂ 413.0295 413.0313 Ex. 120 2-methyl C₂₀H₁₇BrFNO₂ 402.0499402.0502 Ex. 121 2-phenyl C₂₅H₁₉BrFNO₂ 464.0656 464.0654 Ex. 1224-methoxy C₂₀H₁₇BrFNO₃ 418.0449 418.0455 Ex. 123 2-CO₂CH₃ C₂₁H₁₇BrFNO₄446.0398 446.0403

NMR characterization of compounds of Examples 115-123 Example No. NMRData Ex. 115 ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.20 (m, 4H), 7.15-6.85 (m,5H), 6.07 (d, J = 8 Hz, 1H), 5.21 (s, 2H), 5.13 (s, 2H), 3.82 (s, 3H)Ex. 116 ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.20 (m, 4H), 7.10-6.95 (m, 3H),6.11 (d, J = 8 Hz, 1H), 5.19 (s, 2H), 5.14 (s, 2H), 1.32 (s, 9H) Ex. 117¹H NMR (300 MHz, CDCl₃) δ 7.40-6.90 (m, 9H), 6.08 (d, J = 8 Hz, 1H),5.19 (s, 2H), 5.14 (s, 2H), 2.37 (s, 3H) Ex. 118 ¹H NMR (300 MHz, CDCl₃)δ 7.67-7.53 (m, 4H), 7.31-724 (m, 2H), 7.09-6.98 (m, 3H), 6.04 (d, J = 8Hz, 1H), 5.26 (s, 2H), 5.14 (s, 2H) Ex. 119 ¹H NMR (300 MHz, CDCl₃) δ7.71 (dd, J = 8, 2 Hz, 2H), 7.58-7.55 (m, 2H), 7.29-7.25 (m, 2H), 7.90(d, J = 8 Hz, 1H), 7.03-6.98 (m, 2H), 6.03 (dd, J = 8, 2 Hz, 1H), 5.26(s, 2H), 5.15 (s, 2H) Ex. 120 ¹H NMR (300 MHz, CDCl₃) δ 7.45-6.90 (m,9H), 6.15-6.10 (m, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 2.38 (s, 3H) Ex. 121¹H NMR (300 MHz, CDCl₃) δ 7.70-7.65 (m, 1H), 7.55-7.25 (m, 9H) 7.14 (d,J = 8 Hz, 1H), 7.10-6.95 (m, 3H), 5.81 (d, J = 8 Hz, 1H), 5.12 (s, 2H),5.08 (s, 2H) Ex. 122 ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.25 (m, 3H),7.15-6.90 (m, 6H), 6.15-6.10 (m, 1H), 5.16 (s, 2H), 5.14 (s, 2H), 3.82(s, 3H) Ex. 123 ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J = 8, 1 Hz, 1H),7.87 (d, J = 8 Hz, 1H), 7.70-7.60- (m, 1H), 7.50-7.25 (m, 3H), 7.09 (d,J = 8 Hz, 1H), 7.05-6.95 (m, 2H), 6.19 (d, J = 8 Hz, 1H), 5.65 (s, 2H),5.16 (s, 2H), 3.91 (s, 3H)

Example 124

3-Bromo-1-(3-fluorobenzyl)-4-(2-hydroxymethylbenzyloxy)-1H-pyridin-2-oneStep 1. Preparation of3-Bromo-1-(3-fluorobenzyl)-4-(2-hydroxymethylbenzyloxy)-1H-pyridin-2-one

To an ice-cold solution of methyl2-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydro-pyridin-4-yloxymethyl]benzoate(0.12 g, 0.28 mmol) in THF (5 mL) was added LiBH₄ (0.15 mL of a 2.0 Msolution in THF, 0.30 mmol), and the reaction mixture heated at refluxfor 5 hours. The reaction mixture was cooled to room temperature, thesolvent was removed under reduced pressure, and the residue dissolved inEtOAc. The organic solution was washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. ¹H NMR (300 MHz,DMSO-d₆) δ 7.98 (d, J=8 Hz, 1H), 7.46-7.28 (m, 5H), 7.15-7.10 (m, 3H),6.56 (d, J=8 Hz, 1H), 5.35 (s, 2H), 5.25 (br s, 1H), 5.14 (s, 2H).ESHRMS m/z 418.0453 (M+H C₂₀H₁₈BrFNO₃ requires 418.0449).

Example 126

2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}acetamideStep 1. Preparation of (2-Bromomethylphenyl)acetic acid

A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in aceticacid (13 mL) was stirred at room temperature for 2 h, and 70° C. for 1h. The reaction mixture was cooled to room temperature, and poured intoice-water. The precipitate was collected to afford(2-bromomethylphenyl)acetic acid as an off-white solid (2-15 g, 93%): ¹HNMR (300 MHz, DMSO-d₆) δ 7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).

Step 2. Preparation of Methyl (2-Bromomethylphenyl)acetate

To an ice-cold solution of (2-bromomethylphenyl)acetic acid (1 g, 4.4mmol) in THF (2.4 mL) was added trimethylsilyldiazomethane (3 mL of a 2M solution in hexanes, 6 mmol), and the reaction mixture was stirred for14 h. The reaction was quenched with AcOH, and the solvent was removedunder reduced pressure. Purification by flash column chromatography(silica, eluent 98:2 to 94:6 methylene chloride/hexanes) afforded methyl(2-bromomethylphenyl)acetate as a light yellow solid (0.34 g, 32%): ¹HNMR (300 MHz, CDCl₃) δ 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H),3.71 (s, 3H).

Step 3. Preparation ofMethyl{2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}acetate

Methyl{2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}acetatewas prepared by a procedure similar to the one described for EXAMPLE 74(0.41 g, 68%): ¹H NMR (300 MHz, CDCl₃) δ 7.55-6.81 (m, 8H), 6.10 (d, J=6Hz, 1H), 5.20 (s, 4H), 3.78 (s, 2H), 3.60 (s, 3H).

Step 4. Preparation of2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}acetamide

2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}-acetamidewas prepared by a procedure similar to the one described for Example 102(0.07 g, 72%): mp 178-183° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=8Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.54 (br s, 1H), 7.35 (br s, 1H),7.30-7.15 (m, 4H), 6.98 (br s, 1H), 6.85 (d, J=7 Hz, 1H), 6.60 (d, J=8Hz, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 3.62 (s, 2H). ESHRMS m/z 463.0442(M+H C₂₁H₁₈BrF₂N₂O₃ requires 463.0463).

Example 127

Ethyl{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]-phenyl}acetateStep 1. Preparation of Ethyl (3-bromomethylphenyl)acetate

To a mixture of m-tolylacetic acid ethyl ester (3.0 g, 16.8 mmol) andN-bromosuccinimide (3.0 g, 16.8 mmol) was added carbon tetrachloride (45mL), followed by benzoyl peroxide (5 mg), and the reaction mixture washeated at reflux for 16 h. The reaction mixture was cooled to roomtemperature, filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica, eluent 5:95 to 2:3EtOAc/hexanes) afforded ethyl (3-bromomethylphenyl)acetate as anoff-white solid (0.89 g, 21%): ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (m,4H), 4.48 (s, 2H), 4.16 (q, J=6 Hz, 2H), 3.63, (s, 2H), 1.27 (t, J=6 Hz,3H).

Step 2. Preparation ofEthyl{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}acetate

Ethyl{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}-acetatewas prepared by a procedure similar to the one described for EXAMPLE 74(0.27 g, 69%): mp 95-98° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.55 (m,1H), 7.40-7.20 (m, 5H), 7.00-6.80 (m, 2H), 6.09 (d, J=9 Hz, 1H), 5.21(s, 2H), 5.16 (s, 2H), 4.14 (q, J=6 Hz, 2H), 3.60 (s, 2H), 1.25 (t, J=6Hz, 3H). ESHRMS m/z 492.0655 (M+H C₂₃H₂₁BrF₂NO₄ requires 435.0617).

Example 128

2-{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}acetamide

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 102 (0.07 g, 28%): mp 164-167° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.96 (d, J=9 Hz, 1H), 7.70-7.60 (m, 1H), 7.60 (br s,1H), 7.50-7.10 (m, 6H), 6.89 (br s, 1H), 6.58 (d, J=9 Hz, 1H), 5.31 (s,2H), 5.12 (s, 2H), 3.32 (s, 2H). ESHRMS m/z 463.0485 (M+H C₂₁H₁₈BrF₂N₂O₃requires 463.0464).

Example 129

4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-1H-pyridin-2-oneStep 1. Preparation of4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-1H-pyridin-2-one

To a solution of3-bromo-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one(EXAMPLE 107) (0.14 g, 0.32 mmol), K₂CO₃ (88 mg, 0.64 mmol) and Cs₂CO₃(0.10 g, 0.32 mmol) in dioxane (2 mL) was added Pd(PPh₃)₄ (18 mg, 0.12mmol), followed by trimethylboroxine (40 mg, 0.32 mmol). The reactionmixture was degassed, purged with argon, and heated at reflux for 4 h.The reaction mixture was cooled to room temperature, and partitionedbetween water and EtOAc. The organic solution was washed with brine,dried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification by flash column chromatography (silica, eluent methylenechloride to 97:3 methylene chloride/MeOH) afforded4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-1H-pyridin-2-oneas a white solid (0.09 g, 79%): mp 127-129° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.50-7.40 (m, 1H), 7.35-7.25 (m, 1H), 7.17 (d, J=9 Hz, 1H), 7.06 (d,J=6 Hz, 1H), 7.00-6.80 (m, 4H), 6.12 (d, J=9 Hz, 1H), 5.12 (s, 4H), 2.07(s, 3H). ESHRMS m/z 360.1180 (M+H C₂₀H₁₆F₃NO₂ requires 360.1206).

Example 130

4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-3-iodo-1H-pyridin-2-oneStep 1. Preparation of4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one

To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (from Step1, EXAMPLE 110) (0.92 g, 4.2 mmol) and K₂CO₃ (1.15 g, 8.4 mmol) inacetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol),and the reaction mixture was heated at reflux for 3 h. The reactionmixture was cooled to room temperature, concentrated under reducedpressure, and the residue was dissolved in EtOAc. The organic solutionwas washed with water and then brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification by flash columnchromatography (silica, eluent methylene chloride to 95:5 methylenechloride/methanol) provided4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one as a whitesolid (1.21 g, 84%): ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.20 (m, 2H), 7.14(d, J=8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J=3 Hz, 1H), 5.95 (dd, J=5,3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-3-iodo-1H-pyridin-2-one

To a mixture of4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g,0.43 mmol) and N-iodosuccinimide (0.10 g, 0.46 mmol) in CH₃CN (3 mL) wasadded dichloroacetic acid (13 mg, 0.10 mmol), and the reaction mixturewas heated to 60° C. for 4 h. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure, and the residue wasdissolved in methylene chloride. The organic solution was washed with asaturated solution of NaHCO₃ and then brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography (silica, eluent 90:10 methylene chloride/hexanes to 99:1methylene chloride/methanol) provided4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-3-iodo-1H-pyridin-2-one asa white solid (0.15 g, 77%): mp 164-167° C.; ¹H NMR (300 MHz, CDCl₃) δ7.65-7.55 (m, 1H), 7.35-7.26 (m, 2H) 7.15-6.80 (m, 5H), 6.05 (d, J=6 Hz,1H), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 472.0033 (M+H C₁₉H₁₄F₃₁NO₂requires 472.0018).

Example 131

4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carbonitrileStep 1. Preparation of4-Methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile

A solution of 2-(dimethylaminoethoxymethylene)malononitrile (1.97 g) inconcentrated sulfuric acid (7.0 mL) was stirred at room temperature for6.5 h. The reaction mixture was poured into water, and the precipitatewas collected by filtration. ¹H NMR (300 MHz, DMSO d₆) δ 12.14 (br s,1H), 7.79 (d, J=9 Hz, 1H), 6.35 (d, J=9 Hz, 1H), 3.98 (s, 3H).

Step 2. Preparation of1-(3-Fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile

1-(3-Fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrilewas prepared by a procedure similar to the one described for EXAMPLE 74(0.56 g, 93%): ¹H NMR (300 MHz, CDCl₃) δ 7.48 (d, J=9 Hz, 1H), 7.40-7.27(m, 1H), 7.00-6.95 (m, 2H), 6.08 (d, J=9 Hz, 1H), 5.10 (s, 2H), 4.00 (s,3H).

Step 3. Preparation of1-(3-Fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile

To a solution of sodium hydride (92 mg of a 60% dispersion in mineraloil, 2.3 mmol) in DMF (7 mL) was added ethanethiol (0.14 g, 2.2 mmol),followed by a solution of1-(3-fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile(0.23 g, 0.89 mmol) in DMF (2 mL), and the reaction mixture was heatedto 100° C. The reaction mixture was cooled to room temperature,acidified with 3 N HCl, and washed with EtOAc. The organic solution waswashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure to give1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrileas an off-white solid (0.20 g, 91%): ¹H NMR (300 MHz, MeOD) δ 8.00 (s,1H), 7.82 (d, J=8 Hz, 1H), 7.40-7.30 (m, 1H), 7.15-7.00 (m, 2H), 6.13(d, J=8 Hz, 1H), 5.11 (s, 2H).

Step 4. Preparation of4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile

4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrilewas prepared by a procedure similar to the one described for EXAMPLE 107(0.09 g, 30%): mp 187-190° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.45 (m,2H), 7.40-7.30 (m, 1H), 7.10-6.50 (m, 5H), 6.13 (d, J=9 Hz, 1H), 5.27(s, 2H), 5.10 (s, 2H).

Example 132

1-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-1H-pyridin-2-oneStep 1. Preparation of Methyl1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate

To a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g,5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acidbis-(2,4,6-trichloro-phenyl)ester (2.71 g, 5.72 mmol) and the reactionmixture was heated at 170° C. for 3 h. The reaction mixture was cooledto room temperature, and concentrated under reduced pressure.Purification by flash column chromatography (silica, eluent methylenechloride to 94:6 methylene chloride/MeOH) and recrystallization from hotMeOH provided methyl1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylateas pale yellow crystals (0.34 g, 21%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.82(s, 1H), 4.00-3.90 (m, 1H), 3.76 (s, 3H), 2.75-2.60 (m, 2H), 2.31 (s,3H), 1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20 (m,2H), 1.15-1.05 (m, 1H).

Step 2. Preparation of1-Cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid

A solution of methyl1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate(0.35 g, 1.25 mmol) in 2 N NaOH (5 mL) was heated at reflux for 3.5 h.The reaction mixture was cooled room temperature, acidified to pH 1-2with 1 N HCl, and washed with EtOAc. The organic solution was washedwith brine, dried (MgSO₄), filtered and concentrated under reducedpressure to afford1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid as a white solid (0.31 g, 94%): ¹H NMR (300 MHz, MeOD) δ 4.30-4.00(br s, 1H), 2.76 (br s, 5H), 1.90 (s, 3H), 1.90-1.80 (m, 2H), 1.75-1.60(m, 3H), 1.50-1.15 (m, 3H).

Step 3. Preparation of1-Cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one

A solution of1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.15 g, 0.57 mmol) in concentrated HCl (5 mL) was heated at refluxfor 4 h. The reaction mixture was cooled to room temperature, dilutedwith water and washed with EtOAc. The organic solution was washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto give 1-cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one as a whitesolid (0.2 g, 77w): ¹H NMR (300 MHz, DMSO-d₆) δ 9.81 (s, 1H), 5.73 (s,1H), 3.95-3.75 (m, 1H), 2.80-2.55 (m, 2H), 2.25 (s, 3H), 1.85-1.40 (m,5H), 1.72 (s, 3H), 1.38-1.05 (m, 3H).

Step 4. Preparation of1-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-1H-pyridin-2-one

1-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-1H-pyridin-2-one wasprepared by a procedure similar to the one described for EXAMPLE 107(0.05 g, 16%): mp 118-120° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.48-7.41 (m,1H), 6.95-6.81 (m, 2H), 5.87 (s, 1H), 5.07 (s, 2H), 4.05-3.85 (m, 1H),3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.98 (s, 3H), 1.95-1.80 (m, 2H),1.70-1.55 (m, 3H), 1.40-1.20 (m, 3H).

Example 133

3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-pyrazol-4-ylmethyl)-1H-pyridin-2-oneStep 1. Preparation of 4-Methylpyrazole-1-carboxylic acid tert-butylester

To a solution of 4-methyl-1H-pyrazole (1 g, 12 mmol) and DMAP (0.15 g,1.2 mmol) in CH₃CN (20 mL) was added di-tert-butyl dicarbonate (2.8 g,13 mmol), and the reaction mixture was stirred for 1 h. The reactionmixture was concentrated under reduced pressure, and the residuedissolved in EtOAc. The organic solution was washed with 1 N HCl, waterand then brine, dried (MgSO₄), filtered, and concentrated under reducedpressure to provide 4-methyl-pyrazole-1-carboxylic acid tert-butyl esteras a light yellow oil (2.2 g, 100%): ¹H NMR (300 MHz, CDCl₃) δ 7.83 (s,1H), 7.53 (s, 1H), 2.09 (s, 3H), 1.64 (s, 9H).

Step 2. Preparation of 4-Bromomethylpyrazole-1-carboxylic acidtert-butyl ester

To a solution of 4-methylpyrazole-1-carboxylic acid tert-butyl ester(1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was addedN-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg), andthe reaction mixture was heated at reflux for 16 h. The reaction mixturewas cooled to room temperature, filtered, and concentrated under reducedpressure. Purification by flash column chromatography (silica, 1:4EtOAc/hexanes) provided 4-bromomethylpyrazole-1-carboxylic acidtert-butyl ester as a light yellow oil (0.42 g, 30%): ¹NMR (300 MHz,CDCl₃) δ 8.10 (s, 1H), 7.74 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H).

Step 3. Preparation of4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester

4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester was prepared by a procedure similar to the onedescribed for EXAMPLE 632: ¹H NMR (300 MHz, CDCl₃) δ 8.09 (s, 1H), 7.72(s, 1H), 7.53 (app q, J=6 Hz, 1H), 6.97-6.82 (m, 2H), 6.00 (s, 1H), 5.19(s, 2H), 5.13 (s, 2H), 2.43 (s, 3H), 1.63 (s, 9H).

Step 4. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-pyrazol-4-ylmethyl)-1H-pyridin-2-one

4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester (0.16 g, 0.34 mmol) was heated to 140° C. for 16h. The reaction mixture was cooled to room temperature. ¹H NMR (300 MHz,CDCl₃) δ 8.33 (s, 2H), 7.68 (d, J=6 Hz, 1H), 7.52 (app q, J=6 Hz, 1H),6.93-6.83 (m, 2H), 6.47 68 (d, J=9 Hz, 1H), 5.19 (s, 2H), 5.24 (s, 2H),5.20 (s, 2H).

Example 1344-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

Preparation of4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile.3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.0 g,3.6 mmol) was dissolved in N,N-dimethylformamide (5 mL).α-Bromo-p-tolunitrile (0.85 g, 4.3 mmol) was added followed by K₂CO₃(0.59 g, 4.3 mmol). The resulting mixture was heated to 80° C. for 16 h.The reaction was concentrated to an oil that was partitioned betweenwater and ethyl acetate and extracted with ethyl acetate (3×100 ml). Theorganic extracts were combined, washed with brine, dried over Na₂SO₄,and filtered. The filtrate was concentrated to an oil, and purified bychromatography (silica gel, hexane/ethyl acetate) to yield a white solid(0.65 g, 46%). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.4 Hz, 2H),7.41-7.31 (m, 7H), 7.23 (d, J=7.6 Hz, 1H), 6.11 (d, J=8.0 Hz, 1H), 5.24(s, 2H), 5.18 (s, 2H). ES HRMS m/z 395.0404 (M+H C₂₀H₁₅BrN₂O₂ requires395.0390).

Example 1353-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The title compound was prepared by a procedure essentially as describedin example 134. ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.54 (m, 3H), 7.45 (d,J=7.6 Hz, 1H), 7.43-7.31 (m, 5H), 7.26 (d, J=1.6 Hz, 1H), 6.12 (d, J=1.6Hz, 1H), 5.24 (s, 2H), 5.15 (s, 2H). ES HRMS m/z 395.0420 (M+HC₂₀H₁₅BrN₂O₂ requires 395.0390).

Example 1362-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The title compound was prepared by a procedure essentially as describedin example 134. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=8.4 Hz, 1H); 7.63(dd, J=1.2, 8.0 Hz, 1H), 7.57 (dt, J=1.2, 8.4 Hz, 1H), 7.55 (d, J=8.0Hz, 1H); 7.43-7.30 (m, 6H), 6.13 (d, J=8.0 Hz, 1H,), 5.33 (s, 2H), 5.23(s, 2H). ES HRMS m/z 395.0398 (M+H C₂₀H₁₅BrN₂O₂ requires 395.0390).

Example 1371-[4-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one

Preparation of1-[4-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one.EXAMPLE 134 (100 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL)under N₂. Borane dimethylsulfide complex (0.25 mL, 0.5 mmol, 2M intetrahydrofuran) was added. The reaction was then heated to 70° C. andshaken overnight. The mixture was cooled and all the solvent wasdistilled under vacuum. The resulting residue was partitioned betweenethyl acetate and 0.2 N NaOH, and extracted with ethyl acetate (3×10mL). The organic extracts were combined, washed with brine, dried overNa₂SO₄, and filtered. The filtrate was concentrated to an oil, andtriturated with dichloromethane and hexane to give an off-white solid.(80 mg, 80%). ¹H NMR (400 MHz, d₆DMSO) δ 7.90 (d, J=7.6 Hz, 1H);7.43-7.21 (m, 9H), 6.70 (d, J=7.6 Hz, 1H), 5.29 (s, 2H), 5.08 (s, 2H),3.71 (s, 2H). ES HRMS m/z 399.0721 (M+H C₂₀H₁₉BrN₂O₂ requires 399.0703).

Example 1381-[3-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one

The title compound was prepared by a procedure essentially as describedin Example 137 using the title compound of Example 135 as startingmaterial. ¹H NMR (400 MHz, d₆DMSO) δ 7.90 (d, J=7.6 Hz, 1H), 7.44-7.22(m, 9H), 6.50 (d, J=7.6 Hz, 1H), 5.30 (s, 2H), 5.12 (s, 2H), 3.88 (s,2H). ES HRMS m/z 399.0730 (M+H C₂₀H₁₉BrN₂O₂ requires 399.0703).

Example 1391-[2-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one

The title compound was prepared by a procedure essentially as describedin Example 137 using the title compound of Example 136 as startingmaterial. ¹H NMR (400 MHz, d₆DMSO) δ 7.88 (d, J=8.0 Hz, 1H); 7.45-7.34(m, 5H), 7.26-7.21 (m, 3H); 6.85 (d, J=7.2 Hz, 1H), 6.53 (d, J=7.6 Hz,1H), 5.32 (s, 2H), 5.12 (s, 2H), 3.90 (s, 2H) ES HRMS m/z 399.0699 (M+HC₂₀H₁₉BrN₂O₂ requires 399.0703).

Example 1404-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide

Preparation of4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide.EXAMPLE 134 (100 mg, 0.25 mmol) was added to a suspension of potassiumfluoride (40% on alumina) in t-butyl alcohol, heated to 85° C., andstirred for 20 h. The alumina was removed by filtration and washed withdichloromethane and water. The resulting filtrate was separated and theaqueous layer was extracted with dichloromethane (2×20 mL). The organicextracts were combined, dried over Na₂SO₄, and filtered. The filtratewas concentrated to an oil. Trituration with dichloromethane and hexanegave a solid (11.5 mg, 11%). ¹H NMR (400 MHz, d₆DMSO) δ 7.94 (d, J=8.0Hz, 1H), 7.80 (d, J=8.4 Hz, 2H); 7.43-7.29 (m, 7H), 6.51 (d, J=7.6 Hz,1H), 5.31 (s, 2H), 5.16 (s, 2H). ES HRMS m/z 413.0541 (M+H C₂₀H₁₇BrN₂O₃requires 413.0495).

Example 1413-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide

The title compound was prepared by a procedure essentially as describedin Example 140 using the title compound of Example 135 as startingmaterial. ¹H NMR (400 MHz, d₆DMSO) δ 7.95 (d, J=7.6 Hz, 2H), 7.76 (m,2H); 7.43-7.26 (m, 8H), 6.51 (d, J=7.6 Hz, 1H), 5.31 (s, 2H), 5.15 (s,2H). ESHRMS m/z 413.0497 (M+H C₂₀H₁₇BrN₂O₃ requires 413.0495).

Example 1422-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzamide

The title compound was prepared by a procedure essentially as describedin Example 140 using the title compound of Example 136 as startingmaterial. ¹H NMR (400 MHz, d₆DMSO) δ 7.78 (d, J=7.6 Hz, 1H), 7.54 (dd,J=1.6, 7.6 Hz, 1H); 7.45 (d, J=7.6 Hz, 2H); 7.44-7.32 (m, 5H), 7.15 (d,J=7.6 Hz, 1H), 6.49 (d, J=7.6 Hz, 1H), 5.39 (s, 2H), 5.30 (s, 2H). ESHRMS m/z 4413.0506 (M+H C₂₀H₁₇BrN₂O₃ requires 413.0495).

Example 143 Methyl3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate

Preparation of Methyl3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate. EXAMPLE134 (100 mg, 0.25 mmol) was suspended in methanol and cooled to 0° C.HCl (g) was bubbled through the mixture until saturated (˜30 minutes).The reaction was warmed to ambient temperature and stirred for 4 hours.HCl and methanol were removed in vacuo, yielding an oil, that waspurified by chromatography (silica gel, hexane/ethyl acetate) to yield awhite solid (3 mg, 3%). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (app d, J=8.0 Hz,2H), 7.77 (app d, J=8.0 Hz, 1H); 7.55 (app d, J=8.0 Hz, 2H); 7.41-7.35(m, 5H), 6.52 (d, J=7.6 Hz, 1H), 5.31 (s, 2H), 5.27 (s, 2H); 3.88, (s,3H). API-ES MS m/z 429.0 (M+H C₂₁H₁₈BrNO₄ requires 428.0492).

Example 144 Methyl4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}benzoate

The title compound was prepared by a procedure essentially as describedin Example 143 using the title compound of Example 134 as startingmaterial. ¹H NMR (400 MHz, CD₃OD) δ 7.94 (app d, J=8.4 Hz, 2H), 7.76(app d, J=7.6 Hz, 1H); 7.46 (app d, J=8.0 Hz, 2H); 7.39-7.35 (m, 5H),6.51 (d, J=7.6 Hz, 1H), 5.31 (s, 2H), 5.26 (s, 2H); 3.88, (s, 3H). ESHRMS m/z 428.0492 (M+H C₂₁H₁₈BrNO₄ requires 428.0492).

Example 145 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile

Preparation of4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (100 mg,0.36 mmol) was suspended in dimethylsulfoxide (5 mL), cesium carbonate(375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes.4-Fluorobenzonitrile (52 mg, 0.43 mmol was then added, the reaction washeated to 80° C., and stirred. Reaction was monitored by LC/MS, andafter 4 h was heated to 100° C. and stirred for 16 hours. Reactionmixture was partitioned between water and ethyl acetate and extractedwith ethyl acetate (5×50 mL). The organic extracts were combined, washedwith brine, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to an oil, and purified by chromatography (silica gel,hexane/ethyl acetate) to yield a white solid (40 mg, 29%). ¹H NMR (400MHz, CDCl₃) δ 7.77 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.44-7.42(m, 4H), 7.28 (d, J=7.6 Hz, 1H), 7.26 (s, 1H), 6.24 (d, J=7.6 Hz, 1H);5.31, (s, 2H). ES HRMS m/z 381.0230 (M+H C₁₉H₁₃BrN₂O₂ requires381.0233).

Example 146 2-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile

Preparation of2-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (100 mg,0.36 mmol) was suspended in dimethylsulfoxide (5 mL), cesium carbonate(375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes.4-Fluorobenzonitrile (52 mg, 0.43 mmol) was then added and the reactionwas heated to 80° C. with stirring. Reaction was monitored by LC/MS, andafter 4 h was heated to 100° C. and stirred for 16 hours. The reactionmixture was partitioned between water and ethyl acetate and extractedwith ethyl acetate (5×50 mL). The organic extracts were combined, washedwith brine, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to an oil, and purified by chromatography (silica gel,hexane/ethyl acetate) to yield a white solid (18 mg, 13%). ¹H NMR (400MHz, CDCl₃) δ 7.81 (dd, J=1.2, 8.4 Hz, 1H), 7.73 (dt, J=1.2, 8.0 Hz,1H), 7.57 (dt, J=0.8, 8.0 Hz, 1H), 7.50-7.36 (m, 6H), 7.27 (d, J=8.0 Hz,1H), 6.28 (d, J=8.0 Hz, 1H); 5.31 (s, 2H). ES HRMS m/z 381.0249 (M+HC₁₉H₁₃BrN₂O₂ requires 381.0233).

Example 147(4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]methyl}phenyl)aceticacid

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.5 g,1.78 mmol) was dissolved in N,N-dimethylformamide (5 mL).4-(Bromomethyl)phenylacetic acid (0.5 g, 2.14 mmol) was added followedby K₂CO₃ (0.3 g, 2.14 mmol). The reaction was heated to 80° C. andshaken for 16 hours, then heated to 100° C. and shaken for 16 hoursmore. The reaction mixture was partitioned between water and ethylacetate and extracted with ethyl acetate (2×50 mL). The aqueous layerwas acidified (pH 2) with 1N HCl and extracted with ethyl acetate (3×50ml). The organic extracts were combined, washed with brine, dried overNa₂SO₄, and filtered. The filtrate was concentrated to an oil, andpurified by chromatography (silica gel, hexane/ethyl acetate) followedby reversed phase chromatography (C₁₈, 0.1% aqueous trifluoroaceticacid/acetonitrile) to yield a white solid (25 mg, 3%). ¹H NMR (400 MHz,CDCl₃) δ 7.40-7.38 (m, 3H), 7.25-7.20 (m, 7H), 6.05 (d, J=8.0 Hz, 1H),5.21 (s, 2H); 5.13, (s, 2H); 3.62, (s, 2H). ES HRMS m/z 428.0510 (M+HC₂₁H₁₈BrNO₄ requires 428.0492).

Example 148{4-[(4-(benzyloxy)-3-bromo-2-{[4-(carboxymethyl)benzyl]oxy}-1lambda⁵-pyridin-1-yl)methyl]phenyl}aceticacid

Preparation of{4-[(4-(benzyloxy)-3-bromo-2-{[4-(carboxymethyl)benzyl]oxy}-1lambda⁵-pyridin-1-yl)methyl]phenyl}aceticacid. The desired product was isolated by reversed phase chromatography(C₁₈, 0.1% aqueous trifluoroacetic acid/acetonitrile) using thepreparation of Example 147 yielding a white solid (53 mg, 5%). ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.38 (m, 3H), 7.27-7.24 (m, 6H), 7.20 (d, J=7.6Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.06 (d, J=7.6Hz, 1H), 5.21 (s, 2H); 5.11 (s, 2H); 5.11 (s, 2H); 3.63 (s, 2H); 3.58(s, 2H). ES HRMS m/z 576.1009 (M+H C₃₀H₂₈BrNO₆ requires 576.1016).

Example 1492-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

Preparation of2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile.3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(1H)-one (50 mg, 0.15mmol) was dissolved in tetrahydrofuran (2 mL). α-Bromo-o-tolunitrile (44mg, 0.23 mmol) was added followed by sodium hydride (7.2 mg, 0.18 mmol,60% in mineral oil) and sodium iodide (56 mg, 0.38 mmol). The reactionwas heated to 50° C. and stirred for 16 hours. The reaction was filteredthrough Celite® and the filtrate was concentrated to an oil that waspartitioned between water and ethyl acetate and extracted with ethylacetate (4×10 mL). The organic extracts were combined, washed withbrine, dried over MgSO₄, and filtered. The filtrate was concentrated toan oil, and purified by chromatography (silica gel, hexane/ethylacetate) to yield a white solid (25 mg, 37%). ¹H NMR (400 MHz, CDCl₃) δ7.68 (dd, J=8.0, 1.2 Hz, 1H); 7.58 (app q, J=8.8 Hz, 1H); 7.52 (dt,J=8.0 & 1.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H); 7.08 (d, J=8.8 Hz, 1H),7.00-6.93 (m, 1H); 6.89-6.84 (m, 1H); 6.05 (s, 1H), 5.57 (s, 2H), 5.22(s, 2H); 2.28, (s, 3H). ES HRMS m/z 445.0335 (M+H C₂₁H₁₅BrF₂N₂O₂requires 445.0358).

Example 1503-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The title compound was prepared by a procedure essentially as describedin Example 149 using3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(1H)-one (1 g, 3 0mmol) as starting material. ¹H NMR (CDCl₃, 400 MHz) δ 7.61-7.55 (m, 2H);7.45-7.41 (m, 3H); 6.98-6.94 (m, 1H); 6.89 6.84 (m, 1H); 6.03 (s, 1H),5.36 (s, 2H), 5.22 (s, 2H); 2.30, (s, 3H). ES HRMS m/z 445.0349 (M+HC₂₁H₁₅BrF₂N₂O₂ requires 445.0358)

Example 1514-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The title compound was prepared by a procedure essentially as describedin Example 149 using3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(1H)-one (1 g, 3.0mmol) as starting material. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=8.4 Hz,2H); 7.62-7.56 (m, 1H); 7.27 (d, J=8.8 Hz, 2H); 6.95 (app t, J=8.4 Hz,1H), 6.88-6.83 (m, 1H); 6.03 (s, 1H), 5.39 (s, 2H), 5.21 (s, 2H); 2.28(s, 3H). ES HRMS m/z 445.0359 (M+H C₂₁H₁₅BrF₂N₂O₂ requires 445.0358).

Example 1524-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide

Example 151-(50 mg, 0.11 mmol) was added to a suspension or potassiumfluoride (40% on alumina) in t-butyl alcohol. The reaction was heated to90° C. and stirred for 20 hours. Alumina was removed by filtration andwashed with dichloromethane and water. The resulting filtrate wasseparated and the aqueous layer was extracted with dichloromethane (2×20mL). The organic extracts were combined, dried over Na₂SO₄ and filtered.The filtrate was concentrated to an oil which was purified bychromatography (silica gel, hexane/ethyl acetate) to yield a whitesolid, yielding the product (13 mg, 25%). ¹H NMR (400 MHz, CDCl₃) δ 7.75(app d, J=8.4 Hz, 2H), 7.58 (app q, J=8.4 Hz, 1H); 7.24 (d, J=8.4 Hz,2H); 6.98-6.94 (m, 1H), 6.89-6.83 (m, 1H) 6.01 (s, 1H); 5.40 (s, 2H),5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0486 (M+H C₂₁H₁₇BrF₂N₂O₃requires 463.0463).

Example 153 Methyl4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate

Example 151-(50 mg, 0.11 mmol) was suspended in methanol and cooled to0° C. HCl (g) was bubbled through the mixture until saturated (˜30minutes). Reaction was sealed, warmed to ambient temperature, andstirred for 2 hours. HCl and methanol were removed in vacuo, yielding anoil, that was purified by chromatography (silica gel, hexane/ethylacetate) to yield a white solid (19 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ7.97 (app d, J=8.4 Hz, 2H), 7.58 (app q, J=8.0 Hz, 1H); 7.22 (d, J=8.4Hz, 2H); 6.95 (app dt, J=1.5, 9.6 Hz, 1H), 6.89-6.83 (m, 1H), 6.00 (s,1H); 5.41 (s, 2H), 5.21 (s, 2H); 3.90, (s, 3H); 2.27 (s, 3H). ES HRMSm/z 478.0461 (M+H C₂₂H₁₈BrNO₄ requires 478.0460).

Example 154 Methyl3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate

The title compound was prepared by a procedure essentially as describedin Example 149 using the title compound of Example 150 as startingmaterial. ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.92 (m, 1H); 7.84 (bs, 1H);7.58 (app q, J=8.0 Hz, 1H); 7.39-7.37 (m, 2H); 6.95 (app dt, J=1.6, 8.4Hz, 1H), 6.88-6.83 (m, 1H), 6.00 (s, 1H); 5.40 (s, 2H), 5.21 (s, 2H);3.90, (s, 3H); 2.30 (s, 3H). ES HRMS m/z 478.0449 (M+H C₂₂H₁₈BrNO₄requires 478.0460).

Example 1553-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide

The title compound was prepared by a procedure essentially as describedin Example 152 using the title compound of Example 150 as startingmaterial. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 2H), 7.57 (app q,J=8.4 Hz, 1H); 7.42-7.34 (m, 2H); 6.98-6.92 (m, 1H), 6.89-6.83 (m, 1H)6.01 (s, 1H); 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z463.0461 (M+H C₂₁H₁₇BrF₂N₂O₃ requires 463.0463).

Example 1562-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide

The title compound was prepared by a procedure essentially as describedin Example 152 using the title compound of Example 149 as startingmaterial. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 2H), 7.57 (app q,J=8.4 Hz, 1H); 7.42-7.34 (m, 2H); 6.98-6.92 (m, 1H), 6.89 6.83 (m, 1H)6.01 (s, 1H); 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z463.0461 (M+H C₂₁H₁₇BrF₂N₂O₃ requires 463.0463). ¹H NMR (400 MHz, CDCl₃)δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2H); 7.00-6.94 (m, 1H), 6.88-6.84 (m,1H); 6.81-6.79 (m, 1H) 6.11 (s, 1H); 5.51 (s, 2H), 5.24 (s, 2H); 2.43(s, 3H). ESHRMS m/z 463.0467 (M+H C₂₁H₁₇BrF₂N₂O₃ requires 463.0463).

Example 1571-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Example 149 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL)under N₂. Borane-methyl sulfide complex (0.11 mL, 0.22 mmol, 2M intetrahydrofuran) was added. The reaction was then heated to 70° C. andshaken overnight. After cooling to ambient temperature, all the solventwas distilled under vacuum. The resulting residue was partitionedbetween ethyl acetate and 0.2 N NaOH, and extracted with ethyl acetate(3×20 mL). The organic extracts were combined, washed with brine, anddried over Na₂SO₄, and filtered. The filtrate was concentrated to anoil, and purified by chromatography (silica gel, hexane/ethyl acetate)to yield a white solid, to give product (19 mg, 39%). ¹H NMR (400 MHz,CDCl₃) δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2H); 7.00-6.94 (m, 1H),6.88-6.84 (m, 1H); 6.81-6.79 (m, 1H); 6.11 (s, 1H); 5.44 (s, 2H), 5.17(s, 2H); 4.59 (s, 2H); 2.18 (s, 3H). ESHRMS m/z 449.0692 (M+HC₂₁H₁₉BrF₂N₂O₂ requires 449.0671).

Example 1583-bromo-1-[3-(bromomethyl)benzyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Preparation of3-bromo-1-[3-(bromomethyl)benzyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2 g, 6.06mmol) was suspended in 1,4-dioxane (250 mL). α,α′-Dibromo-m-xylene (8 g,30.3 mmol) was added followed by sodium hydride (0.3 g, 7.5 mmol, 60% inmineral oil). The reaction was heated to 60° C. and stirred for 16hours. The reaction was filtered through Celite® and the filtrate wasconcentrated to an oil that was partitioned between water anddichloromethane and extracted with dichloromethane (4×250 mL). Theorganic extracts were combined, washed with brine, dried over Na₂SO₄,and filtered. The filtrate was concentrated to an oil, and purified bychromatography (silica gel, hexane/ethyl acetate) to yield a white solid(1.2 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (app q, J=7.6 Hz, 1H);7.28-7.25 (m, 2H); 7.17 (s, 1H); 7.08 (m, 1H); 6.94 (app dt, J=1.2, 9.6Hz, 1H), 6.87-6.82 (m, 1H); 5.99 (s, 1H), 5.34 (s, 2H), 5.20 (s, 2H);4.43 (s, 2H); 2.29 (s, 3H). ES HRMS m/z 511.9672 (M+H C₂₁H₁₇Br₂F₂NO₂requires 511.9667).

Example 1593-bromo-1-[4-(bromomethyl)benzyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure essentially as describedin Example 158. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 2H), 7.57 (appq, J=8.4 Hz, 1H); 7.42-7.34 (m, 2H); 6.98-6.92 (m, 1H), 6.89-6.83 (m,1H) 6.01 (s, 1H); 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z463.0461 (M+H C₂₁H₁₇BrF₂N₂O₃ requires 463.0463). ¹H NMR (400 MHz, CDCl₃)δ 7.56 (app q, J=7.6 Hz, 1H); 7.32 (d, J=8.0 Hz, 2H); 7.14 (d, J=8.0 Hz,2H); 6.94 (app t, J=8.4 Hz, 1H), 6.87-6.82 (m, 1H); 5.98 (s, 1H), 5.33(s, 2H), 5.19 (s, 2H); 4.44 (s, 2H); 2.29 (s, 3H). ES HRMS m/z 511.9683(M+H C₂₁H₁₇Br₂F₂NO₂ requires 511.9667).

Example 1601-[4-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Example 159 (200 mg, 0.39 mmol) was suspended in methanol (3 mL) andcooled to −78° C. Ammonia (g) was bubbled through the mixture for 30minutes. The reaction vessel was sealed, allowed to reach ambienttemperature, and stirred for 4 hours. The solvent and ammonia wereremoved from the reaction in vacuo with stirring and the resulting oilwas triturated with ether to yield a solid (174 mg, 99%). ¹H NMR (400MHz, CD₃OD) δ 7.61 (q, J=7.6 Hz, 1H); 7.40 (d, J=8.0 Hz, 2H); 7.20 (d,J=8.0 Hz, 2H); 7.03 (app t, J=8.8 Hz, 2H), 6.51 (s, 1H), 5.43 (s, 2H),5.29 (s, 2H); 4.07 (s, 2H); 2.36 (s, 3H). ES HRMS m/z 449.0673(C₂₁H₁₉BrF₂N₂O₂ requires 449.0671).

Examples 161-168

The compounds of Examples 161-168 are prepared essentially according tothe procedures set forth above for Examples 158-160 or by using thecompound of Example 158:

Example M + H ESHRMS No. R MF Requires m/z Ex. 161 —NH₂ C₂₁H₁₉BrF₂N₂O₂449.0671 449.0694 Ex. 162 morpholin-4-yl C₂₅H₂₅BrF₂N₂O₃ 519.1089519.1132 Ex. 163 dimethylamino C₂₃H₂₃BrF₂N₂O₂ 477.0984 477.0991 Ex. 164isopropylamino C₂₄H₂₅BrF₂N₂O₂ 491.1140 491.1121 Ex. 165 piperidin-1-ylC₂₆H₂₇BrF₂N₂O₂ 517.1297 517.1341 Ex. 166 (2-hydroxyethyl)-C₂₃H₂₃BrF₂N₂O₃ 493.0933 493.0961 amino Ex. 167 bis(2-hydroxy-C₂₅H₂₇BrF₂N₂O₄ 537.1195 537.1171 ethyl)amino Ex. 168 piperazin-1-ylC₂₅H₂₆BrF₂N₃O₂ 518.1249 518.1280

NMR characterization of compounds of Examples 161-168 Ex. No. NMR DataEx. 161 ¹H NMR (400 MHz, CD₃OD) δ 7.61 (q, J = 7.6 Hz, 1H); 7.42-7.35(m, 2H), 7.24-7.20 (m, 2H), 7.03 (app t, J = 8.4 Hz, 2H), 6.51 (s, 1H),5.43 (s, 2H), 5.29 (s, 2H); 4.07 (s, 2H); 2.04 (s, 3H) Ex. 162 ¹H NMR(400 MHz, CD₃OD) δ 7.58 (app q, J = 7.6 Hz, 1H); 7.26-7.22 (m, 2H), 7.15(s, 2H), 7.01 (app d, J = 6.4 Hz, 2H), 6.95 (app dt, J = 1.2, 8.0 Hz,1H); 6.88-6.82 (m, 1H); 5.98 (s, 1H), 5.35 (s, 2H), 5.20 (s, 2H); 3.69(t, J = 8.4 Hz, 4H); 3.46 (s, 2H); 2.41 (m, 4H); 2.29 (s, 3H) Ex. 163 ¹HNMR (400 MHz, CD₃OD) δ 7.61 (app q, J = 7.6 Hz, 1H); 7.25-7.14 (m, 3H);7.01-6.92 (m, 2H); 6.85 (m, 1H); 5.97 (s, 1H), 5.36 (s, 2H), 5.20 (s,2H); 3.38 (s, 2H); 2.28 (s, 3H); 2.21 (s, 6H) Ex. 164 ¹H NMR (400 MHz,CDCl₃) δ 7.61 (app q, J = 8.0 Hz, 1H); 7.25-7.22 (m, 2H); 7.14 (s, 1H),6.99 (app d, 6.8 Hz, 1H), 6.94 (app dt, J = 2.0, 8.0 Hz, 1H), 6.88-6.80(m, 1H); 5.97 (s, 1H), 5.34 (s, 2H), 5.19 (s, 2H); 3.73 (s, 2H); 2.28(s, 3H); 2.82 (app heptet, J = 6.0 Hz, 1H), 1.07 (d, J = 6.0 Hz, 6H) Ex.165 ¹H NMR (400 MHz, CD₃OD) δ 7.61 (app q, J = 8.0 Hz, 1H); 7.27 (app t,J = 8.0 Hz, 1H); 7.20 (app d, J = 7.6 Hz, 1H); 7.08 (bs, 1H); 7.01 (appt, J = 8.0 Hz, 2H); 6.48 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H); 3.44 (s,2H); 2.35 (s, 3H); 2.40-2.30 (m, 4H); 1.57-1.53 (m, 4H); 1.48-1.38 (m,2H) Ex. 166 ¹H NMR (400 MHz, CDCl₃) δ 7.51 (app q, J = 8.0 Hz, 1H);7.22-7.14 (m, 3H); 7.09 (bs, 1H); 6.98 (app d, J = 7.2 Hz, 1H); 6.89(app dt, J = 1.6, 8.0 Hz, 1H); 6.81-6.76 (m, 1H); 5.92 (s, 1H), 5.28 (s,2H), 5.14 (s, 2H); 3.73 (s, 2H); 3.59 (app t, J = 4.8 Hz, 2H); 2.73 (appt, J = 4.8 Hz, 2H); 2.24 (s, 3H) Ex. 167 ¹H NMR (400 MHz, CD₃OD) δ 7.61(app q, J = 8.0 Hz, 1H); 7.46 (app d, J = 8.8 Hz, 2H); 7.31 (bs, 1H);7.27 (app t, J = 8.0 Hz, 1H); 7.03 (app t, J = 8.8 Hz, 2H); 6.54 (s,1H), 5.44 (s, 2H), 5.30 (s, 2H); 4.47 (s, 2H); 3.90-3.84 (m, 4H);3.40-3.25 (m, 4H); 2.40 (s, 3H) Ex. 168 ¹H NMR (400 MHz, CD₃OD) δ 7.62(app q, J = 8.0 Hz, 1H); 7.53-7.46 (m, 2H); 7.36 (bs, 1H); 7.30 (app d,J = 7.6 Hz , 1H); 7.05-7.01 (m, 2H); 6.55 (s, 1H), 5.44 (s, 2H), 5.30(s, 2H); 4.47 (s, 2H); 3.58-3.53 (m, 8H); 2.42 (s, 3H)

Example 1693-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid

Preparation of3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid. EXAMPLE 154 (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran(5 mL). Potassium trimethylsilanolate (80 mg, 0.62 mmol) was added andthe reaction was stirred at ambient temperature for 4 hours. Thereaction mixture was concentrated to an oil that was partitioned betweenwater and ethyl acetate and extracted with ethyl acetate. The organicextracts were combined, washed with brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to an oil and purified byreversed phase chromatography (C₁₈, 0.1% aqueous trifluoroaceticacid/acetonitrile) to yield the product (64 mg, 44%) ¹H NMR (400 MHz,CD₃OD) δ 7.92 (app d, J=8.0 Hz, 1H); 7.78 (s, 1H); 7.62 (app q, J=8.0Hz, 1H); 7.44 (t, J=7.6 Hz, 1H); 7.36 (app d, J=8.0 Hz, 1H); 7.02 (appt, J=7.6 Hz, 2H); 6.51 (s, 1H), 5.48 (s, 2H), 5.30 (s, 2H); 2.37 (s,3H). ES HRMS m/z 464.0328 (C₂₁H₁₆BrF₂NO₄ requires 464.0304).

Examples 170-174

The compounds of Examples 170-174 are prepared using the compound ofExample 159 or 161:

Example M + H ESHRMS No. R MF Requires m/z Ex. 170 —C(O)CH₃C₂₃H₂₁BrF₂N₂O₃ 491.0776 491.0772 Ex. 171 —C(O)OCH₃ C₂₃H₂₁BrF₂N₂O₄507.0726 507.0731 Ex. 172 —SO₂CH₃ C₂₂H₂₁BrF₂N₂O₄S 527.0446 527.0430 Ex.173 —C(O)CH₂OH C₂₃H₂₁BrF₂N₂O₄ 507.0726 507.0712 Ex. 174 —C(O)NH₂C₂₂H₂₀BrF₂N₃O₃ 492.0729 492.0751

NMR characterization of compounds of Examples 170-174 Ex. No. NMR DataEx. 170 ¹H NMR (400 MHz, CD₃OD) δ 7.61 (app q, J = 8.0 Hz, 1H); 7.28(app t, J = 8.0, 1H), 7.18 (app d, J = 8.0 Hz, 1H), 7.05-7.00 (m, 4H);6.49 (s, 1H), 5.41 (s, 2H), 5.29 (s, 2H); 2.37 (s, 3H); 1.94 (s, 3H) Ex.171 ¹H NMR (400 MHz, CDCl₃) δ 7.57 (app q, J = 7.6 Hz, 1H); 7.25 (app t,J = 8.0, 1H), 7.17 (app d, J = 8.0 Hz, 1H), 7.06-7.02 (m, 2H); 6.97-6.91(m, 1H); 6.87-6.82 (m, 1H), 5.98 (s, 1H), 5.33 (s, 2H), 5.19 (s, 2H);4.30 (d, J = 6.0 Hz, 2H); 3.67 (s, 3H); 2.28 (s, 3H) Ex. 172 ¹H NMR (400MHz, CD₃CN) δ 7.58 (app q, J = 7.6 Hz, 1H); 7.31 (app t, J = 8.0, 1H),7.24 (app d, J = 8.0 Hz, 1H), 7.11 (s, 1H); 7.05-7.00 (m, 3H); 6.32 (s,1H), 6.06 (bs, 1H), 5.31 (s, 2H), 5.23 (s, 2H); 4.17 (d, J = 6.4 Hz,2H); 2.78 (s, 3H); 2.28 (s, 3H) Ex. 173 ¹H NMR (400 MHz, CDCl₃) δ 7.55(app q, J = 8.0 Hz, 1H); 7.23 (app t, J = 7.6, 1H), 7.15 (app d, J = 7.2Hz, 1H), 7.05-7.00 (m, 3H); 6.94 (app dt, J = 1.2, 8.8 Hz, 1H);6.88-6.81 (m, 1H); 6.03 (s, 1H), 5.27 (s, 2H), 5.19 (s, 2H); 4.39 (d, J= 6.4 Hz, 2H); 4.05 (s, 2H), 2.31 (s, 3H) Ex. 174 ¹H NMR (400 MHz,CD₃OD) δ 7.62 (app q, J = 8.0 Hz, 1H); 7.28 (app t, J = 8.0, 1H), 7.19(app d, J = 8.0 Hz, 1H), 7.05-6.96 (m, 4H); 6.49 (s, 1H), 5.41 (s, 2H),5.29 (s, 2H); 4.25 (s, 2H); 2.35 (s, 3H)

Examples 175-185

The compounds of Examples 175-175 are prepared using the compounds ofExamples 159 or 160:

Example M + H ESHRMS No. R MF Requires m/z Ex. 175 —CH₂NHCH(CH₃)₂C₂₄H₂₅BrF₂N₂O₂ 491.1140 491.1143 Ex. 176 morpholin-4-ylmethylC₂₅H₂₅BrF₂N₂O₃ 519.1089 519.1062 Ex. 177 —CH₂N(CH₃)₂ C₂₃H₂₃BrF₂N₂O₂477.0984 477.0931 Ex. 178 piperidin-1-ylmethyl C₂₆H₂₇BrF₂N₂O₂ 517.1297517.1258 Ex. 179 [bis(2- C₂₅H₂₇BrF₂N₂O₄ 537.1195 537.1181hydroxyethyl)amino]- mehtyl Ex. 180 —CH₂NHCH₂CH₂OH C₂₃H₂₃BrF₂N₂O₃493.0933 493.0907 Ex. 181 piperazin-1- C₂₅H₂₆BrF₂N₃O₂ 518.1249 518.1213ylmethyl Ex. 182 —CH₂NHC(O)OCH₃ C₂₃H₂₁BrF₂N₂O₄ 507.0726 507.0752 Ex. 183—CH₂NHC(O)CH₃ C₂₃H₂₁BrF₂N₂O₃ 491.0776 491.0793 Ex. 184 —CH₂NHSO₂CH₃C₂₂H₂₁BrF₂N₂O₄S 527.0446 527.0431 Ex. 185 —CH₂NHC(O)NH₂ C₂₂H₂₀BrF₂N₃O₃492.0729 492.0720

NMR characterization of compounds of Examples 175-185 Ex. No. NMR DataEx. 175 ¹H NMR (400 MHz, CDCl₃) δ 7.56 (q, J = 8.0 Hz, 1H); 7.25 (d, J =8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.94 (app t, J = 8.0 Hz, 1H),6.88-6.80 (m, 1H); 5.97 (s, 1H), 5.31 (s, 2H), 5.19 (s, 2H); 3.74 (s,2H); 2.82 (app heptet, J = 6.0 Hz, 1H), 2.28 (s, 3H); 1.09 (d, J = 6.4Hz, 6H) Ex. 176 ¹H NMR (400 MHz, CDCl₃) δ 7.56 (q, J = 8.0 Hz, 1H); 7.25(d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.94 (app dt, J = 2.0,8.0 Hz, 1H), 6.87-6.81 (m, 1H); 5.97 (s, 1H), 5.33 (s, 2H), 5.19 (s,2H); 3.67 (app t, J = 4.8 Hz, 4H); 3.44 (s, 2H); 2.44-2.38 (m, 4H), 2.29(s, 3H) Ex. 177 ¹H NMR (400 MHz, CDCl₃) δ 7.56 (q, J = 8.0 Hz, 1H); 7.23(d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.93 (app dt, J = 2.0,8.0 Hz, 1H), 6.86-6.81 (m, 1H); 5.96 (s, 1H), 5.33 (s, 2H), 5.18 (s,2H); 3.38 (s, 2H); 2.29 (s, 3H); 2.20 (s, 6H) Ex. 178 ¹H NMR (400 MHz,CDCl₃) δ 7.56 (q, J = 8.0 Hz, 1H); 7.24-7.20 (m, 2H), 7.10-7.07 (m, 2H),6.96-6.90 (m, 1H), 6.86-6.81 (m, 1H); 5.96 (s, 1H), 5.32 (s, 2H), 5.18(s, 2H); 3.34 (s, 2H); 2.31 (s, 3H); 2.31-2.28 (m, 4H); 1.53-1.51 (m,4H); 1.39 (m, 2H) Ex. 179 ¹H NMR (400 MHz, CDCl₃) δ 7.57 (q, J = 8.0 Hz,1H); 7.25 (d, J = 8.0 Hz, 2H); 7.12 (d, J = 8.0 Hz, 2H); 6.94 (dt, J =8.8 Hz, 2H); 6.87-6.82 (m, 1H), 5.98 (s, 1H), 5.33 (s, 2H), 5.19 (s,2H); 3.68 (s, 2H); 3.61 (t, J = 5.2 Hz, 4H); 2.70 (t, J = 5.2 Hz, 4H);2.29 (s, 3H) Ex. 180 ¹H NMR (400 MHz, CDCl₃) δ 7.57 (q, J = 8.0 Hz, 1H);7.25 (d, J = 8.0 Hz, 2H); 7.12 (d, J = 8.0 Hz, 2H); 6.94 (app dt, J =8.8 Hz, 2H); 6.87-6.82 (m, 1H), 5.98 (s, 1H), 5.33 (s, 2H), 5.19 (s,2H); 3.68 (s, 2H); 3.61 (t, J = 5.2 Hz, 4H); 2.70 (t, J = 5.2 Hz, 4H);2.29 (s, 3H) Ex. 181 ¹H NMR (400 MHz, CDCl₃) δ 7.61 (q, J = 8.0 Hz, 1H);7.52 (d, J = 8.0 Hz, 2H); 7.25 (d, J = 8.0 Hz, 2H); 7.03 (app t, J = 8.0Hz, 2H); 6.53 (s, 1H), 5.44 (s, 2H), 5.30 (s, 2H); 4.32 (bs, 2H);3.55-3.35 (m, 8H); 2.39 (s, 3H) Ex. 182 ¹H NMR (400 MHz, CDCl₃) δ 7.56(app q, J = 8.0 Hz, 1H); 7.20 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz,2H), 6.94 (app dt, J = 1.2, 8.0 Hz, 1H), 6.87-6.81 (m, 2H); 5.97 (s,1H), 5.32 (s, 2H), 5.19 (s, 2H); 4.31 (d, J = 6.0 Hz, 2H); 3.68 (s, 3H);2.28 (s, 3H) Ex. 183 ¹H NMR (400 MHz, CDCl₃) δ 7.61 (app q, J = 8.0 Hz,1H); 7.23 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.04-6.99 (m,2H); 6.47 (s, 1H), 5.39 (s, 2H), 5.28 (s, 2H); 4.30 (s, 2H); 2.34 (s,3H); 1.95 (s, 3H) Ex. 184 ¹H NMR (400 MHz, CD₃OD) δ 7.62 (app q, J = 8.0Hz, 1H); 7.34 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.02 (appt, J = 8.8 Hz, 2H), 6.48 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H); 4.21 (s,2H); 2.82 (s, 3H); 2.35 (s, 3H) Ex. 185 ¹H NMR (400 MHz, d₇DMF) δ 7.76(app q, J = 8.0 Hz, 1H); 7.28 (d, J = 8.0 Hz, ), 7.14 (d, J = 8.0 Hz,2H), 7.34-7.26 (m, 1H); 7.22-7.14 (m, 1H); 6.62 (s, 1H), 5.65 (s, 2H),5.39 (s, 2H), 5.37 (s, 2H); 4.26 (d, J = 6.0 Hz, 2H); 2.40 (s, 3H)

Example 1864-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoyl)piperazine-1-carboxamide

3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H)-one(300 mg, 0.54 mmol) was dissolved in N,N-dimethylacetamide (5 mL).Trimethylsilyl isocyanate (0.15 mL, 1.08 mmol) was added followed byN,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and the reaction wasstirred for 1 hour at ambient temperature. The reaction was then dilutedwith tetrahydrofuran (40 mL) and polyamine resin (1.3 g, 2.81 mmol/g)and methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g) wereadded. The mixture was shaken for 6 hours, filtered, and the resultingfiltrate was concentrated to a white solid (279 mg, 90%). ¹H NMR (400MHz, CD₃OD) δ 7.61 (app q, J=8.0 Hz, 1H); 7.41 (d, J=8.0 Hz, 2H), 7.23(d, J=8.0 Hz, 2H), 7.03 (app t, J=8.8 Hz, 2H); 6.51 (s, 1H), 5.46 (s,2H), 5.30 (s, 2H), 3.75-3.35 (m, 8H); 2.37 (s, 3H) ES HRMS m/z 575.1104(C₂₆H₂₅BrF₂N₄O₄ requires 575.1100).

Example 187N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-2-methoxyacetamide

Polymer bound carbodiimide resin (2.3 g, 1.18 meq/g, 2.7 mmol) wassuspended in N,N-dimethylformamide. Acetoxyacetic acid (120 mg, 1.33mmol) was added, followed by 1-hydroxybenzotriazole (1M inN,N-dimethylformamide, 0.165 mL) and N,N-diisopropylethylamine (0.3 mL,2.0 mmol). The reaction was shaken for 1 hour when EXAMPLE 159 (300 mg,0.67 mmol) was added. The reaction was shaken for 16 hours and thendiluted with tetrahydrofuran. Polyamine resin (1 g, 2.81 mmol/g) andmethylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) wereadded and the mixture was shaken for 72 hours, filtered and theresulting filtrate concentrated. Trituration with water followed bytrituration with ether yielded a white solid (125 mg, 36%). ¹H NMR (400MHz, CDCl₃) δ 7.56 (app q, J=8.0 Hz, 1H); 7.21 (d, J=8.0 (Hz, 2H), 7.13(d, J=8.0 Hz, 2H), 6.94 (app t, J=8.8 Hz, 1H), 6.88-6.81 (m, 1H); 5.97(s, 1H), 5.33 (s, 2H), 5.19 (s, 2H); 4.43 (d, J=6.0 Hz, 2H); 3.92 (s,2H); 3.39 (s, 3H); 2.29 (s, 3H). ES HRMS m/z 521.0882 (C₂₄H₂₂BrF₂N₂O₄requires 521.0882).

Examples 188-193

By following the general method for the preparation of Example 187 andsubstituting the appropriate carboxylic acid for acetoxyacetic acid, thecompounds of Examples 188-193 are prepared. These compounds weretriturated with water and again with ether and purified bychromatography (silica gel, hexane/ethyl acetate) as appropriate toyield off-white solids. Example 191 was prepared from itsN-t-butoxycarbonyl protected intermediate. Deprotection was accomplishedwith 4N HCl in dioxane to afford the title compound as its hydrochloridesalt (86 mg, 24%). Deprotection of the methyl ester from Ex. 188 wasaccomplished with K₂CO₃ in methanol/water to yield Ex. 192 as a whitesolid. The yields and analytical data are shown below.

Compound % M + H ESHRMS No. R Yield MF Requires m/z Ex. 188 CH₂OCOCH₃ 49C₂₅H₂₃BrF₂N₂O₅ 549.0831 549.0849 Ex. 189 C(CH₃)₂OH 13 C₂₅H₂₅BrF₂N₂O₄535.1039 535.1035 Ex. 190 C(—CH₂CH₂—)OH 33 C₂₅H₂₃BrF₂N₂O₄ 535.0865535.0876 Ex. 191 CH₂NH₂ 24 C₂₃H₂₂BrF₂N₃O₃ 533.0882 533.0899 Ex. 192CH₂OH 25 C₂₃H₂₁BrF₂N₂O₄ 507.0726 507.0730 Ex. 193 CH₂NHCOCH₃ 81C₂₅H₂₄BrF₂N₃O₃ 548.0991 548.1000

Example 1941-{4-[(4-acetylpiperazin-1-yl)carbonyl]benzyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H)-one(200 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL).N,N-Diisopropylethylamine (0.25 mL, 1.44 mmol) was added followed byacetic anhydride (0.10 mL, 1.06 mmol). The reaction was stirred for 2hours at ambient temperature. and concentrated to an oil that wastriturated in ether and again in water to yield an off-white solid (131mg, 63%) ¹H NMR (400 MHz, CD₃OD) δ 7.62 (app q, J=8.0 Hz, 1H); 7.42 (d,J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.62-7.02 (m, 1H); 7.02 (app t,J=8.0 Hz, 1H); 6.52 (s, 1H), 5.46 (s, 2H), 5.30 (s, 2H); 3.80-3.65 (m,8H); 2.37 (s, 3H); 2.11 (s, 3H). ES HRMS m/z 574.1150 (C₂₇H₂₆BrF₂N₃O₄requires 574.1148).

Example 1953-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(4-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}benzyl)pyridin-2(1H)-one

3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H)-one(300 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (5mL)-4-Methylmorpholine (0.23 mL, 2.2 mmol) was added followed bymethanesulfonyl chloride (0.10 mL, 1.33 mmol) and the reaction wasstirred for 2 h. The reaction was then diluted with tetrahydroturan (40mL) and polyamine resin (1.3 g, 2.81 mmol/g) and methylisocyanatefunctionalized polystyrene (1 g, 1.38 mmol/g) were added. The mixturewas shaken for 16 hours, filtered, and the resulting filtrateconcentrated to an oil that was triturated with water. The resultingwhite solid was collected, washed with ether and dried (172 mg, 52%). ¹HNMR (400 MHz, CDCl₃) δ 7.57 (app q, J=8.2 Hz, 1H); 7.34 (d, J=8.0 Hz,2H), 7.20 (d, J=8.0 Hz, 2H), 7.02 (app dt, J=1.2, 8.8 Hz, 1H), 6.88 6.82(m, 1H); 6.02 (s, 1H), 5.37 (s, 2H), 5.21 (s, 2H); 3.80-3.20 (m, 8H);2.79 (s, 3H); 2.30 (s, 3H). ES HRMS m/z 610.0851 (C₂₆H₂₆BrF₂N₃O₅Srequires 610.0817).

Example 196Methyl-4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzoate

Step 1. Preparation of4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile

4-benzyloxy-2(1H)-pyridone (12.00 g, 59.63 mmol) was dissolved indimethyl sulfoxide (100 mL). Potassium carbonate (10.99 g, 79.50 mmol)was added, followed by 4-fluorobenzonitrile (4.81 g, 39.75 mmol). Thereaction was stirred at 100° C. for 18 hours. After cooling to roomtemperature the reaction was diluted with H₂O (150 mL) and the solidswere collected by filtration washing with diethyl ether. Chromatography(silica gel, hexanes/ethyl acetate) provided an off-white solid (7.78 g,65%). ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.5Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, J=13.3, 1H), 6.13 (dd, J=2.6, 7.7Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 5.07 (s, 2H).

Step 2. Preparation of4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile

4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile (Step 1) (2.76 g,9.13 mmol) was suspended in acetonitrile (50 mL) and cooled in anice-bath. N-bromosuccinimide (1.71 g, 9.54 mmol) was added. Once theaddition was complete the cooling bath was removed. After stirring for45 minutes the reaction was diluted with acetonitrile and solids werecollected by filtration to give a white solid (3.13 g, 90%). ¹H NMR (300MHz, DMSO-d₆) δ 8.00 (d, J=8.5 Hz, 2H), 7.84 (d, J=7.9 Hz, 1H), 7.66 (d,J=8.5, 2H), 7.50-7.37 (m, 5H), 6.63 (d, J=7.9 Hz, 1H), 5.41 (s, 2H).

Step 3. Preparation ofmethyl-4-[4-(benzyl)oxy-3-bromo-2-oxopyridin-1(2H)-yl]benzoate.4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzonitrile (Step 2)(1.50 g, 3.93 mmol) suspended in methanol (50 mL) was cooled in anice-bath. HCl (g) was then bubbled through the mixture for 5 minutes.The reaction was then stirred at room temperature overnight, at whichtime the reaction mixture was concentrated. The residue was suspended in6N HCl (60 mL) and heated at reflux for 1.5 hours. After cooling to roomtemperature the solids were collected by filtration. Chromatography(silica gel, hexanes/ethyl acetate) provided an off-white shiny solid(0.540 g, 61%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=8.5 Hz, 2H), 7.81(d, J=7.8 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.47-7.39 (m, 5H), 6.57 (d,J=7.9 Hz, 1H), 5.38 (s, 2H), 3.86 (s, 3H). ES-HRMS m/z 416.0355 (M+Hcaldc for C₂₀H₁₆BrNO₄ requires 414.0341).

Example 197 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzoic acid

Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzoicacid EXAMPLE 196 (0.460 g, 1.11 mmol) was dissolved in tetrahydrofuran(5.0 mL). Potassium trimethylsilanolate (0.285 g, 2.22 mmol) was added.The reaction was stirred at room temperature for 3 hours at which timeH₂O (10 mL) was added. The aqueous reaction mixture was acidified (pH-3)with 1N HCl. The tetrahydrofuran was evaporated, additional H₂O (50 mL)was added and the aqueous layer was extracted with ethyl acetate (2×50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and evaporated to provide a rust colored solid(0.444 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) ε8.02 (d, J=8.6 Hz, 2H), 7.80(d, J=7.8 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.50-7.34 (m, 5H), 6.57 (d,J=7.9 Hz, 1H), 5.38 (s, 2H) ES-HRMS m/z 400.0191 (M+H calcd forC₁₉H₁₄BrNO₄ requires 400.0184).

Example 198 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzamide

Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzamide.STEP 2, EXAMPLE 196 (0.238 g, 0.624 mmol) was suspended in tert-butylalcohol (3.0 mL). KF on 40 wt % Al₂O₃ (0.453 g, 3.12 mmol) was added.The reaction mixture was heated at reflux for 5 days. Additional KF on40 wt % Al₂O₃ (0.453 g, 3.12 mmol) was added and heating was continuedat reflux overnight. After cooling to room temperature chloroform andmethanol were added and the solids were collected by filtration.Chromatography (reverse-phase, acetonitrile/H₂O) provided a tan solid(0.073 g, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ8.07 (s, 1H), 7.95 (d, J=8.6Hz, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.47-7.34 (m, 7H), 6.56 (d, J=7.9 Hz,1H), 5.38 (s, 2H). ES-HRMS m/z 399.0372 (M+H calcd for C₁₉H₁₅BrN₂O₃requires 399-0344).

Example 1991-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one

Preparation of1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one. STEP2, EXAMPLE 196 (1.25 g, 3.28 mmol) was dissolved in tetrahydrofuran (15mL). Borane-dimethylsulfide (3.44 mL, 6.89 mmol, 2.0 M intetrahydrofuran) was added and the mixture heated at reflux. After 14.5hours the solvent was evaporated. 0.5M NaOH (50 mL) was added followedby ethyl acetate. The aqueous layer was neutralized with 1N HCl.Methanol saturated with HCl was added and the mixture was heated atreflux for 5 hours. After cooling to room temperature, diethyl ether wasadded and the solids were collected by filtration. The solids weretreated with 4N HCl in dixoane (5 mL) and methanol (1 mL) at roomtemperature for 1 hour, at which time diethyl ether was added and thesolids were collected by filtration to give a tan solid (0.920 g, 67%).¹H NMR (300 MHz, DMSO-d₆) δ8.67 (br s, 2H), 7.76 (d, J=7.6 Hz, 1H), 7.64(d, J=8.3 Hz, 2H), 7.50-7.37 (m, 7H), 6.56 (d, J=7.6 Hz, 1H), 5.41 (s,2H), 4.09 (br s, 2H) ES-HRMS m/z 385.0555 (M+H calcd for C₁₉H₁₇BrN₂O₂requires 385.0552).

Example 200Methyl-4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxypyridin-1(2H)-yl]benzoate

Step 1. Preparation of4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile

4-benzyloxy-2(1H)-pyridone (50.0 g, 248.47 mmol) was dissolved indimethyl sulfoxide (300 mL). Potassium carbonate (68.68 g, 496.94 mmol)was added, followed by 4-fluorobenzonitrile (31.60 g, 260.89 mmol). Thereaction was stirred at 100° C. for 20 hours. After cooling to roomtemperature the reaction was diluted with H₂O (600 mL) and the solidswere collected by filtration washing with diethyl ether. The solids werethen washed with hot methanol to provide a tan solid (55.6 g, 74%). ¹HNMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H),7.44-7.41 (m, 5H), 7.22 (d, J=13.3, 1H), 6.13 (dd, J=2.6, 7.7 Hz, 1H),6.06 (d, J=2.6 Hz, 1H), 5.07 (s, 2H).

Step 2. Preparation of 1-[4-nitrilephenyl]-4-hydroxy-2(1H)-pyridinone

4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]benzonitrile (Step 1) (20.0 g,66.15 mmol) was dissolved in methanol (300 mL). Ammonium formate (8.34g, 132.3 mmol) was added followed by 5% Pd/C (6.62 g). The resultingmixture was heated at reflux for 20 minutes at which time the reactionbegan to exotherm. The reaction was allowed to cool to room temperatureat which time it was filtered through a pad of Celite® washing withmethanol. The filtrate was evaporated to provide a pale yellow solid(16.2 g, >100%). ¹H NMR (300 MHz, CDCl₃) δ8.46 (s, 1H), 7.95 (d, J=8.5Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.47 (d, J=7.7 Hz, 1H), 5.98 (dd,J=2.6, 7.7 Hz, 1H), 5.54 (d, J=2.4 Hz, 1H).

Step 3. Preparation of4-[4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-1(2H)-yl]benzonitrile

1-[4-Nitrilephenyl]-4-hydroxy-2(1H)-pyridinone (Step 2) (16.2 g) wasdissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (10.06g, 72.77 mmol) was added followed by α-bromo-2,4-difluorotoluene (8.91mL, 69.46 mmol). The resulting mixture was heated to 65° C. for 1 hour.Additional α-bromo-2,4-difluorotoluene (4.25 mL, 33.08 mmol) was added.The resulting mixture was heated to 65° C. for 5 hours. Additionalα-bromo-2,4-difluorotoluene (2.12 mL, 16.54 mmol) was added. Afterstirring at 65° C. overnight the reaction was allowed to cool to roomtemperature. H₂O (300 mL) was added and the solid was collected byfiltration. A portion (8.0 g) of the solids were washed with hotmethanol to give a pale yellow solid (6.22 g, 78%). ¹H NMR (300 MHz,CDCl₃) δ8.00 (d, J=8.5 Hz, 2H), 7.72-7.64 (m, 2H) 7.66 (d, J=8.5 Hz,2H), 7.40-7.32 (m, 1H), 7.22-7.16 (m, 1H), 6.17-6.11 (m, 2H), 5.17 (s,2H).

Step 4. Preparation ofmethyl-4-[4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]benzoate

4-[4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-1(2H)-yl]benzonitrile (Step3) (2.00 g, 5.91 mmol) suspended in methanol (20 mL) and H₂O (5 mL) wascooled in an ice-bath. HCl (g) was bubbled through the mixture untilmost of the solids dissolved. The resulting mixture was then heated atreflux for 3 hours. The reaction was then recooled in an ice-bath andHCl was bubbled through the mixture for 5 minutes. The mixture washeated at reflux for 2 hours and then the methanol was evaporated.Additional H₂O (50 mL) was added and the aqueous reaction mixture wasextracted with ethyl acetate (50 mL) and tetrahydrofuran (50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and evaporated. Chromatography (silica gel,hexanes/ethyl acetate with 10% methanol) gave an off-white solid (0.630g, 29%). ¹H NMR (300 MHz, DMF-d₆) δ8.15 (d, J=8.5 Hz, 2H), 7.80 (app q,J=7.9 Hz, 1H), 7.74-7.67 (m, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.42-7.34 (appdt, J=2.4, 9.0 Hz, 1H), 7.28-7.22 (m, 1H), 6.20 (dd, J=2.6, 7.6 Hz, 1H),6.15 (d, J=2.4 Hz, 1H), 5.28 (s, 2H), 3.98 (s, 3H).

Step 5. Preparation ofmethyl-4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxypyridin-1(2H)-yl]benzoate.Methyl-4-[4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]benzoate(Step 4) (0.520 g, 1.40 mmol) was suspended in acetonitrile (10.0 mL).N-chlorosuccinimide (0.196 g, 1.47 mmol) was added followed by severaldrops of dichloroacetic acid. The resulting mixture was heated at refluxovernight. After cooling to room temperature additional acetonitrile wasadded and the precipitate was collected by filtration to give an offwhite solid (0.331 g, 58%). ¹H NMR (300 MHz, DMF-d₆) δ8.34 (d, J=8.5 Hz,2H), 8.12 (d, J=7.9 Hz, 1H), 8.04-7.96 (m, 1H), 7.88 (d, J=8.5 Hz, 2H),7.59-7.53 (m, 1H), 7.52-7.41 (m, 1H), 7.05 (d, J=7.9 Hz, 1H), 5.70 (s,2H), 4.15 (s, 3H). ES-HRMS m/z 406.0644 (M+H calcd for C₂₀H₁₄ClF₂NO₄requires 406.0652).

Example 2013-Bromo-4-[(2,4-difluororbenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one

Step 1. Preparation of4-Hydroxy-1-[3-(hydroxymethyl)phenyl]6-methylpyridin-2(1H)-one

4-hydroxy-6-methyl-2-pyrone (10.0 g, 79.3 mmol) and 3 aminobenzylalcohol (9.77 g, 79.3 mmol) were combined in H₂O (100 mL) and heat atreflux. After 48 hours at reflux the reaction mixture was concentrated.The residue was treated with methanol and the precipitate was collectedby filtration to give a pale yellow solid (3.04 g, 17%). ¹H NMR (300MHz, DMSO-d₆) δ 10.6 (br s, 1H), 7.46-7.35 (m, 2H), 7.09-7.03 (m, 2H),5.88 (d, J=1.6 Hz, 1H), 5.55 (d, J=2.6 Hz, 1H), 4.54 (d, J=4.2 Hz, 2H),1.83 (s, 3H).

Step 2. Preparation of1-[3-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

4-Hydroxy-1-[3-(hydroxymethyl)phenyl]6-methylpyridin-2(1H)-one (Step 1)(0.674 g, 2.91 mmol) was suspended in acetone (10 mL). Cesium carbonate(1.04 g, 3.21 mmol) was added followed by α-bromo-2,4-difluorotoluene(0.392 mL, 3-06 mmol). After stirring at room temperature for 2 days thereaction was concentrated. The residue was portioned between H₂O (30 mL)and ethyl acetate (30 mL). The aqueous layer was further extracted withethyl acetate (30 mL). The combined organic layers were washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated.Chromatography (on silica, hexanes/ethyl acetate with 10% methanol)provided a white solid (0.531 g, 51%). ¹H NMR (300 MHz, CDCl₃) δ7.51-7.39 (m, 3H), 7.82 (s, 1H), 7.16 (d, J=26.8 Hz, 1H), 7.08-6.86 (m,2H), 6.00 (d, J=2.6 Hz, 1H), 5.92 (d, J=2.6 Hz, 1H), 5.05 (s, 2H), 4.68(s, 2H), 1.93 (s, 3H). ES-HRMS m/z 358.1256 (M+H calcd for C₂₀H₁₇F₂NO₃requires 358.1249).

Step 3. Preparation of3-bromo-4-[(2,4-difluororbenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one.1-[3-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(Step 2) (0.460 g, 1.29 mmol) was suspended in acetonitrile (5.0 mL) andcooled in an ice-bath. N-bromosuccinimide (0.241 g, 1.35 mmol) wasadded. Once the addition was complete the cooling bath was removed.After stirring for 1.5 hours the reaction was diluted with acetonitrileand solids were collected by filtration to give a white solid (0.385 g,68%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.70 (app q, J=7.9 Hz, 1H), 7.49-7.32(m, 3H), 7.24-7.10 (m, 3H), 6.66 (s, 1H), 5.35 (s, 2H), 4.56 (d, J=5.6Hz, 2H), 1.95 (s, 3H). ES-HRMS m/z 436.0384 (M+H calcd for C₂₀H₁₆BrF₂NO₃requires 436.0354).

Example 202Methyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Step 1. Preparation of Methyl 4-(4-hydroxy-6-methyl2-oxypyridin-1(2H)-yl)benzoate

4-hydroxy-6-methyl-2-pyrone (21.00 g, 166.70 mmol) and4-methylaminobenzoate (25.20 g, 166.70 mmol) were combined in1,2-dichlorobenzene (50 mL) and rapidly heated to 160° C. After 15minutes at 160° C. the reaction was allowed to cool to room temperature.The reaction was diluted with dichloromethane (50 mL) and extracted withsaturated Na₂CO₃ (2×100 mL). The combined aqueous layers were acidified(pH-2) with concentrated HCl. The precipitate was collected byfiltration and washed with diethyl ether to give a yellow/orange solid(10.9 g, 25%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.8 (s, 1H), 8.07 (d, J=8.5Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 5.95 (d, J=2.4 Hz, 1H), 5.61 (d, J=2.4,1H), 3.91 (s, 3H), 1.85 (s, 3H).

Step 2. Preparation ofMethyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl 4-(4-hydroxy-6-methyl-2-oxypyridin-1(2H)-yl)benzoate (Step 1)(10.90 g, 42.04 mmol) was dissolved in N,N-dimethylformamide (100 mL).Potassium carbonate (6.97 g, 50.45 mmol) was added, followed by2,4-difluorobenzyl bromide (5.66 mL, 44.14 mmol). The reaction wasstirred at room temperature for 3 days then diluted with H₂O (100 mL).The reaction mixture was extracted into ethyl acetate andtetrahydrofuran (2×100 mL). The precipitate was collected by filtrationand the organic filtrate was washed with brine (50 mL), dried overNa₂SO₄, filtered and evaporated. The resulting solid was combined withthe precipitate to provide a pale pink solid (6.77 g, 42%). ¹H NMR (300MHz, DMSO-d₆) 68.01 (d, J=8.3 Hz, 2H), 7.67 (q, J=7.9 Hz, 1H), 7.43 (d,J=8.3 Hz, 2H), 7.35 (m, 1H), 7.18 (app dt, J=1.6, 8.5 Hz, 1H), 6.08 (d,J=1.8 Hz, 1H), 5.98 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 3.91 (s, 3H), 1.87(s, 3H).

Step 3. Preparation ofmethyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(Step 2) (6.74 g, 17.49 mmol) suspended in acetonitrile (100 mL) wascooled in an ice-bath. N-bromosuccinimide (3.27 g, 18.36 mmol) wasadded. After 1 hour the ice-bath was removed and after an additional 30minutes the reaction was diluted with acetonitrile (20 mL). Theprecipitate was collected by filtration to provide the title compound asan off-white solid (6.94 g, 85%). ¹H NMR (300 MHz, CDCl₃) δ8.20 (d,J=8.7 Hz, 2H), 7.61 (q, J=7.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 7.02-6.96(m, 1H), 6.90 (app dt, J=2.4, 9.5 Hz, 1H), 6.14 (s, 1H), 5.28 (s, 2H),3.98 (s, 3H), 2.00 (s, 3H). ES-HRMS m/z 464.0304 (M+H calcd forC₂₁H₁₆BrF₂NO₄ requires 464.0301).

Example 2034-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoicacid

Example 202 (7.43 g, 16.00 mmol) was dissolved in tetrahydrofuran (40mL). Potassium trimethylsilanolate (4.10 g, 32.00 mmol) was added andthe reaction mixture was stirred at room temperature for 22 hours. Thetetrahydrofuran was evaporated and H₂O (50 mL) was added. The aqueousreaction mixture was acidified with 1N HCl and the precipitate wascollected by filtration. The solids were washed with boiling methanol togive an off-white solid (5.05 g, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ 13.2(br s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.72 (q, J=7.9 Hz, 1H), 7.45 (d,J=8.3 Hz, 2H), 7.38 (app dt, J=2.4, 9.9 Hz, 1H), 7.23 (app dt, J=1.8,8.5 Hz, 1H), 6.72 (s, 1H), 5.37 (s, 2H), 1.97 (s, 3H). ES-HRMS m/z450.0154 (M+H calcd for C₂₀H₁₄BrF₂NO₄ requires 450.0147).

Example 2044-(Benzyloxy)-1-(3-fluorobenzyl)-3-(trifluoromethyl)pyridin-2(1H)-one

The starting material (0.250 g, 0.591 mmol) was dissolved in1-methyl-2-pyrrolidinone (5.0 mL). Trifluoroacetic acid, sodium salt(0.322 g, 2.36 mmol) was added, followed by copper(I) iodide (0.225 g,1.18 mmol). The resulting mixture was heated to 180° C. for 5 hours andthen allowed to cool to room temperature. The reaction was diluted withH₂O (50 mL) and brine (50 mL), then extracted into ethyl acetate (2×50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and evaporated. Chromatography (reverse-phase,acetonitrile/H₂O) provided an off-white solid (0.050 g, 22%). ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.27 (m, 8H), 7.06 (d, J=7.7 Hz, 1H), 6.97 (d,J=9.0 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 5.20 (s, 2H), 5.06 (s, 2H).ES-HRMS m/z 378.1097 (M+H calcd for C₂₀H₁₅F₄NO₂ requires 378.1112).

Example 2054-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid

Example 153 (50.0 g, 104.54 mmol) was dissolved in methanol (500 mL) anddioxane (100 mL). 1N NaOH (130 mL, 130 mmol) was added. The resultingmixture was heated to 50° C. for 5.5 hours. The reaction was partiallyconcentrated and the heterogenous mixture was acidified (pH 2) with 1NHCl. The precipitate was collected by filtration to afford a white solid(49.2 g, >100%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J=8.3 Hz, 2H),7.70 (app q, J=7.9 Hz, 1H), 7.35 (dt, J=2.2, 9.9 Hz, 1H), 7.18 (app d,J=8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.64 (s, 1H), 5.41 (s, 2H), 5.33 (s,2H), 2.32 (s, 3H). ES-HRMS m/z 464.0327 (M+H calcd for C₂H₁₆BrF₂NO₄requires 464.0304).

Example 2063-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(hydroxymethyl)benzyl]-6-methylpyridin-2(1H)-one

Example 205 (40.0 g, 86.16 mmol) suspended in tetrahydrofuran (300 mL)was cooled in an ice-bath. Borane dimethylsulfide (129.2 mL, 258.48mmol, 2.0 M in tetrahydrofuran) was slowly added. The resulting mixturewas slowly allowed to warm to room temperature overnight. The mixturewas recooled in an ice-bath and quenched by the addition of small piecesof ice. After the evolution of gas ceased additional ice-water wasadded. The flask was fitted with a distillation apparatus and thedimethylsulfide was removed. After the reaction was cooled to roomtemperature, H₂O (300 mL), ethyl acetate (200 mL) and tetrahydrofuran(300 mL) were added. The precipitate that formed was collected byfiltration and the filtrate was placed in a separatory funnel. Theaqueous layer was further extracted with ethyl acetate (300 mL). Thecombined organic layers were washed with brine (300 mL). The organicphase was dried over Na₂SO₄ and evaporated which was combined with theprecipitate to yield an off-white solid (37.8 g, 97%). ¹H NMR (400 MHz,CDCl₃) δ 7.47 (app q, J=7.7 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.05 (d,J=7.9 Hz, 2H), 6.86 (app dt, J=2.3, 8.6 Hz, 1H), 6.79 (app dt, J=2.4,8.4 Hz, 1H), 6.00 (s, 1H), 5.28 (s, 2H), 5.16 (s, 2H), 4.57 (s, 2H),2.25 (s, 3H). ES-HRMS m/z 450.0512 (M+H calcd for C₂₁H₁₈BrF₂NO₃ requires450.0511).

Example 2073-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1-hydroxy-1-methylethyl)benzyl]-6-methylpyridin-2(1H)-one

Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1-hydroxy-1-methylethyl)benzyl]-6-methylpyridin-2(1H)-one.EXAMPLE 153 (2.00 g, 4.18 mmol) suspended in tetrahydrofuran (20 mL) wascooled in the dry ice/acetone bath. Methyl magnesium bromide (4.32 mL,12.96 mmol, 3.0 M in diethyl ether) was slowly added. The reaction wasslowly allowed to warm to room temperature overnight. The reaction wasthen cooled in an ice bath and quenched by the addition of saturatedNH₄Cl (50 mL). H₂O was added and the reaction was extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated. The residue was subjected tochromatography (silica gel, hexanes/ethyl acetate with 10% methanol) toprovide an off-white foam. The foam was dissolved in acetonitrile andcooled in an ice bath. N-bromosuccinimide (0.057 g, 0.320 mmol) wasadded. Once the addition was complete the cooling bath was removed.After 2.5 hours at room temperature the reaction was concentrated.Purification by chromatography (silica gel, hexanes/ethyl acetate with10% methanol) provided a white foam. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (appq, J=7.7 Hz, 1H), 7.39 (d, J=78.3 Hz, 2H), 7.11 (d, J=8.2 Hz, 2H), 6.92(app dt, J=1.7, 8.4 Hz, 1H), 6.86-6.81 (m, 1H), 5.97 (s, 1H), 5.31 (s,2H), 5.18 (s, 2H), 2.29 (s, 3H), 1.52 (s, 6H). ES-HRMS m/z 478.0811 (M+HC₂₃H₂₂BrF₂NO₃ requires 478.0824).

Example 2083-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{4-[(methylamino)methyl]benzyl}pyridin-2(1H)-one

Step 1. Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzaldehyde

Example 206 (1.30 g, 2.89 mmol) was suspended in acetonitrile (10 mL)and cooled in an ice-bath.1-hydroxy-1,3-dihydro-3,3-bis(trifluoromethyl)-1,2-benziodoxole 1-oxide(0.580 g, 1.44 mmol) was added and the reaction mixture was stirred atroom temperature overnight. Diethyl ether was added and the solid wascollected by filtration to give a white solid (1.14 g, 88%). ¹H NMR (400MHz, CDCl₃) δ9.96 (s, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.56 (app q, J=7.7Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.93 (app dt, J=1.6, 8.3 Hz, 1H),6.87-6.82 (m, 1H), 6.02 (s, 1H), 5.41 (s, 2H), 5.20 (s, 2H), 2.27 (s,3H).

Step 2.3-bromo-4-[(2,4-diflurobenzyl)oxy]-6-methyl-1-[(4-[(methylamino)methyl]benzyl]pyridin-2(1H)-one.4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzaldehyde(Step 1) (1.53 g, 3.41 mmol) of step 1 was dissolved inN,N-dimethylformamie (5.0 mL). Methylamine (3.41 mL, 6.83 mmol, 2.0 M intetrahydrofuran) was added followed by NaHB(OAc) 3 (2.17 g, 10.23 mmol)in N,N-dimethylformamide (8.0 mL) and acetic acid (2.0 mL). The reactionwas stirred at room temperature overnight at which time 1N NaOH (50 mL)was added and then extracted with ethyl acetate (2×50 mL). The organiclayers were washed with brine (25 mL), dried over Na₂SO₄ and evaporated.Chromatography (on silica, ethyl acetate with 5% methanolicammonia/hexanes) afforded a tan solid (0.810 g, 53%). ¹H NMR (400 MHz,CDCl₃) δ 7.55 (app q, J=7.8 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.11 (d,J=8.1 Hz, 2H), 6.92 (app dt, J=2.4, 8.3 Hz, 1H), 6.90-6.80 (m, 1H), 5.95(s, 1H), 5.32 (s, 2H), 5.17 (s, 2H), 3.68 (s, 2H), 2.40 (s, 3H), 2.27(s, 3H). ES-HRMS m/z 463.0838 (M+H calcd for C₂₂H₂₁BrF₂N₂O₄ requires463.0827).

Example 209 4-[(2,4-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2-(1H)-one

Step 1. Preparation of1-(4-methoxybenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

4-Hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and4-methoxybenzylamine (5.00 g, 36.45 mmol) in H₂O (100 mL) were heated toreflux. After 15 hours at reflux the reaction was allowed to cool toroom temperature. The precipitate was collected by filtration washingwith H₂O to give a pale yellow solid (8.00 g, 89%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.2 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 5.74 (d, J=2.0Hz, 1H), 5.56 (d, J=2.5 Hz, 1H), 5.08 (s, 2H), 3.68 (s, 3H), 2.14 (s,3H).

Step 2. Preparation of4-[(2,4-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one.1-(4-methoxybenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (Step 1) (7.97g, 32.49 mmol) was dissolved in N,N-dimethylformamide (60 mL). Potassiumcarbonate (4.94 g, 35.74 mmol) was added, followed byα-bromo-2,4-difluorotoluene (4.38 mL, 34.11 mmol). The reaction wasstirred at room temperature for 20 hours at which time the mixture wasfiltered through a pad of Celite® washing with acetonitrile and thefiltrate was evaporated. The residue was dissolved in H₂O (150 mL) andextracted into ethyl acetate (2×100 mL). The organic phase was washedwith brine (100 mL), dried over Na₂SO₄, filtered and evaporated.Chromatography (on silica, hexanes/ethyl acetate with 10% methanol)yielded an off-white solid (3.64 g, 30%). ¹H NMR (300 MHz CDCl₃) δ 7.42(app q, J=7.7 Hz, 1H), 7.13 (d, J=8.5 Hz, 2H), 6.96-6.84 (m 2H), 6.85(app d, J=8.7 Hz, 2H), 6.01 (d, J=2.6 Hz, 1H), 5.82 (d, J=2.8 Hz, 1H),5.23 (s, 2H), 5.02 (s, 2H), 3.79 (s, 3H), 2.25 (s, 3H). ES-HRMS m/z372.1412 (M+H C₂₁H₁₉F₂NO₃ requires 372.1417).

Example 2103-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one

Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one.EXAMPLE 209 (0.200 g, 0.538 mmol) suspended in acetonitrile (3 mL) wascooled in an ice-bath. N-bromosuccinimide (0.101 g, 0.565 mmol) wasadded. Once the addition was complete the cooling bath was removed.After 1 hour the reaction was concentrated. Purification bychromatography (silica gel, hexanes/ethyl acetate) provided a whitesolid (0.240 g, 99%). ¹H NMR (300 MHz, CDCl₃) δ 7.59 (app q, J=7.8 Hz,1H), 7.16 (d, J=8.7 Hz, 2H), 6.97 (app dt, J=2.4, 8.6 Hz, 1H), 6.91-6.83(m, 1H), 6.85 (app d, J=8.7 Hz, 2H), 5.98 (s, 1H), 5.31 (s, 2H), 5.21(s, 2H), 3.79 (s, 3H), 2.34 (s, 3H). ES-HRMS m/z 450.0491 (M+HC₂₁H₁₈BrF₂NO₃ requires 450.0511).

Example 2113-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(4-hydroxybenzyl)-6-methylpyridin-2(1H)-one

Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(4-hydroxybenzyl)-6-methylpyridin-2(1H)-one.EXAMPLE 210 (0.235 g, 0.522 mmol) was suspended in acetonitrile (3 mL).Cerric ammonium nitrate (1.14 g, 2.09 mmol) dissolved in H₂O (1 mL) wasadded. The reaction was stirred at room temperature for 1 hour and thendiluted with dichloromethane (25 mL). The reaction was then washed withH₂O (10 mL). The aqueous phase was back extracted with dichloromethane(20 mL). The combined organic layers were dried over Na₂SO₄, filteredand evaporated. The residue was washed with hot ethyl acetate to give anoff-white solid (0.134 g, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ7.75 (app q,J=7.9 Hz, 1H), 7.65 (s, 1H), 7.45-7.36 (m, 1H), 7.36 (d, J=10.1 Hz, 2H),7.27-7.20 (m, 1H), 6.49 (d, J=10.1 Hz, 2H), 5.60 (s, 2H), 5.07 (s, 2H),2.63 (s, 3H). ES-HRMS m/z 436.0187 (M+H C₂₀H₁₆BrF₂NO₃ requires436.0354).

Example 2123-bromo-4-[(2,4-difluorobenzyl)oxy]-1{4-[(4-hydroxy-4-methylpiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(1H)-one

Step 1. Preparation of 4-hydroxy-4-methylpiperidine hydrochloride

tert-Butyl-4-oxo-1-piperidine (10.0 g, 50.19 mmol) dissolved in diethylether (100 mL) was cooled in an ice-bath. Methyl magnesium bromide(18.40 mL, 55.21 mmol, 3.0 M in diethyl ether) was added. After slowlywarming to room temperature the reaction was recooled in an ice-bath andquenched by the addition of saturated NH₄Cl (75 mL). Additional H₂O wasadded and the organic layer was removed. The aqueous layer was furtherextracted with diethyl ether (50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated.Chromatography (silica gel, hexanes/ethyl acetate) provided a clear oil.The resulting oil was dissolved in diethyl ether (10 mL) and treatedwith 4N HCl/dioxane (32.61 mL, 130.43 mmol). After stirring at roomtemperature for 1 hour the reaction mixture was concentrated to give apale yellow solid (5.05 g, >100%).

Step 2. Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1{[(4-[(4-hydroxy-4-methylpiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(1H)-one.THE ACID (0.300 g, 0.646 mmol) was suspended in dichloromethane (6.0mL). 1-hydroxybenzotriazole (0.044 g, 0.323 mmol) was added followed by3-(1-cyclohexylcarbodiimide)propyl-functionalized silica gel (2.02 g,1.29 mmol, loading=0.64 mmol/g), 3-(1-morpholine)propyl functionalizedsilica gel (1.84 g, 1.29 mmol, loading=0.7 mmol/g) and dichloromethane(2 mL). After stirring at room temperature for 15 minutes,4-hydroxy-4-methylpiperidine hydrochloride (0.147 g, 0.969 mmol) wasadded. The resulting mixture was stirred at room temperature overnight,at which time dimethylamine-3-functionalized silica gel (1.7 g, 2.58mmol, loading=1.5 mmol/g) was added followed byisocyanate-3-functionalized silica gel (1.3 g, 1.62 mmol, loading=1.22mmol/g). The resulting mixture was stirred at room temperature for 3hours. The reaction mixture was then filtered and concentrated.Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol)provided a white foam (0.200 g, 55%). ¹H NMR (300 MHz, CDCl₃) δ 7.58(app q, J=7.7 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H),6.96 (app t, J=8.3 Hz, 1H), 6.87 (app dt, J=2.0, 9.5 Hz, 1H), 6.06 (s,1H), 5.38 (s, 2H), 5.22 (s, 2H), 4.27 (br m, 1H), 3.41 (br m, 3H), 2.30(s, 3H), 2.06 (s, 1H), 1.60 (br m, 4H), 1.28 (s, 3H). ES-HRMS m/z561.1173 (M+H C₂₇H₂₇BrF₂N₂O₄ requires 561.1195).

Example 2134-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxypyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide

The title compound was by a procedure essentially as in Example 212using 1-amino-2-methyl-2-propanol hydrochloride as starting material.

¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=83 Hz, 2H), 7.53 (app q, J=7.8 Hz,1H), 7.33 (t, J=5.8 Hz, 1H), 7.06 (d, J=8.3 Hz, 2H), 6.95-6.90 (m, 1H),6.86-6.81 (m, 1H), 6.04 (s, 1H), 5.30 (s, 2H), 5.19 (s, 2H), 3.40 (d,J=5.9 Hz, 2H), 2.98 (br s, 1H), 2.24 (s, 3H), 1.21 (s, 6H). ES-HRMS m/z535.1012 (M+H C₂₅H₂₅BrF₂N₂O₄ requires 535.1039).

Example 2143-bromo-4-[(2,4-difluorobenzyl)oxy]-1{4-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(1H)-one

The title compound was produced essentially as in Example 212 using4-hydroxypiperidine as starting material. ¹H NMR (400 MHz, CDCl₃) δ 7.55(app q, J=7.7 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H),6.94 (app dt, J=2.4, 8.4 Hz, 1H), 6.84 (app ddd, J=2.6, 8.9, 10.3 Hz,1H), 6.01 (s, 1H), 5.36 (s, 2H), 5.19 (s, 2H), 4.12-4.07 (m, 1H),3.96-3.90 (m, 1H), 3.60 (br s, 1H), 3.33 (br s, 1H), 3.13 (br s, 1H),2.27 (s, 3H), 1.91 (br s, 3H), 1.77 (br s, 1H), 1.57 (br s, 1H), 1.44(br s, 1H). ES-HRMS m/z 547.1006 (M+H C₂₆H₂₅BrF₂N₂O₄ requires 547.1039).

Example 2154-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)benzamide

Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)benzamide.To a reaction vessel (borosilicate culture tube) was added EXAMPLE 205(0.300 g, 0.646 mmol). A stock solution of 1-hydroxybenzotriazole inN,N-dimethylformamide (3 mL, 0.11 M) was added to the reaction vesselfollowed by approximately 1.10 g of the polymer bound carbodiimide resin(1.8 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added tothe reaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. Ethanolamine (0.06 mL, 0.994 mmol) wasthen added to the reaction vessel and the reaction apparatus wasorbitally shaken at room temperature overnight. At this time thereaction was diluted with tetrahydrofuran (20 mL) and treated withapproximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately2.6 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) andthe orbital shaking was continued at 200 RPM at room temperature for 3hours. The reaction vessel was then opened and the solution phaseproduct was separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partially evaporation theinsoluble byproducts were rinsed further with tetrahydrofuran (2×10 mL)and combined with the partially reduced filtrate. The resulting filtratewas concentrated by blowing N₂ over the vial while heating (60° C.) in areaction block (KEM-Lab Parallel Reactor) to give an off-white solid.(0.111 g, 34%) ¹H NMR (400 MHz, DMF-d₆) δ 8.45 (t, J=5.4 Hz, 1H), 7.94(d, J=8.2 Hz, 2H), 7.76 (app q, J=7.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.27(app d, J=7.9 Hz, 2H), 7.20 (app dt, J=2.4, 8.6 Hz, 1H), 6.65 (s, 1H),5.47 (s, 2H), 5.38 (s, 2H), 4.83 (br s, 1H), 3.64-3.60 (m, 2H),2.47-3.42 (m, 2H), 2.40 (s, 3H). ES-HRMS m/z 507.0742 (M+HC₂₃H₂₁BrF₂N₂O₄ requires 507.0726).

Example 216-231 Preparation of3-bromo-4-(2,4-difluorophenoxy)-6-methyl-1-[4-(aminocarbonyl)benzyl]pyridin-2(1H)-onecompounds

By following the method of Example 215 and substituting the appropriateamine, the compounds of Examples 216-231 are prepared. The deprotectionof the protected intermediates was accomplished with 4N HCl in dioxaneto afford the compounds as hydrochloride salts.

Compound % M + H ESHRMS No. R₁ R₂ Yield MF Requires m/z Ex. 216CH₂CH₂NH— CH₂CH₂NH— 73 C₂₅H₂₄BrF₂N₃O₄ 532.1042 532.1024 Ex. 217 HCH₂CH₂NH₂ 49 C₂₃H₂₂BrF₂N₃O₃ 506.0885 506.0883 Ex. 218 H CH₂CH₂CH₂NH₂ 31C₂₄H₂₄BrF₂N₃O₃ 520.1042 520.1042 Ex. 219 H OH 53 C₂₁H₁₇BrF₂N₂O₄ 479.0413479.0423 Ex. 220 H CH₃ 59 C₂₂H₁₉BrF₂N₂O₄ 477.0620 477.0605 Ex. 221 CH₃CH₃ 51 C₂₃H₂₁BrF₂N₂O₃ 491.0776 491.0794 Ex. 222 CH₂CH₂O— CH₂CH₂O— 61C₂₅H₂₃BrF₂N₂O₄ 533.0882 533.0901 Ex. 223 CH₂CH₂OH CH₂CH₂OH 69C₂₅H₂₅BrF₂N₂O₅ 551.0988 551.0978 Ex. 224 CH₂CH₂CH₂— CH₂CH₂CH₂— 66C₂₆H₂₅BrF₂N₂O₃ 531.1084 531.1089 Ex. 225 H CH(CH₃)₂ 50 C₂₄H₂₃BrF₂N₂O₃505.0933 505.0901 Ex. 226 CH₂CH₂— CH₂CH₂— 71 C₂₅H₂₃BrF₂N₂O₃ 517.0933517.0908 Ex. 227 CH₂CH₂N(CH₃)— CH₂CH₂N(CH₃)— 83 C₂₆H₂₆BrF₂N₃O₃ 546.1198546.1215 Ex. 228 H CH₂CH₂N(CH₃)₂ 81 C₂₅H₂₆BrF₂N₃O₃ 534.1198 534.1197 Ex.229 H CH₂CH₂OCH₃ 79 C₂₄H₂₃BrF₂N₂O₄ 521.0882 521.0861 Ex. 230 CH₃CH₂CH₂OH 36 C₂₄H₂₃BrF₂N₂O₄ 521.0882 521.0893 Ex. 231 CH₃ CH₂CH₂OCH₃ 82C₂₅H₂₅BrF₂N₂O₄ 535.1039 535.1028

Example 2324-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)benzamide

Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)benzamide.To a reaction vessel (borosilicate culture tube) was added EXAMPLE 203(0.300 g, 0.666 mmol). A stock solution of 1-hydroxybenzotriazole inN,N-dimethylformamide (3 mL, 0.11 M) was added to the reaction vesselfollowed by approximately 1.13 g of the polymer bound carbodiimide resin(1.8 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added tothe reaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. Ethanolamine (0.06 mL, 0.994 mmol) wasthen added to the reaction vessel and the reaction apparatus wasorbitally shaken at room temperature overnight. At this time thereaction was diluted with tetrahydrofuran (20 mL) and treated withapproximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately2.7 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) andthe orbital shaking was continued at 200 RPM at room temperature for 3hours. The reaction vessel was then opened and the solution phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partially evaporation theinsoluble byproducts were rinsed further with tetrahydrofuran (2×10 mL)and combined with the partially reduced filtrate. The resulting filtratewas concentrated by blowing N₂ over the vial while heating (60° C.) in areaction block (KEM-Lab Parallel Reactor). Purification bychromatography (silica gel) provided an off-white solid (0.155 g, 47%).¹H NMR (400 MHz, DMF-d₆) δ 8.58 (t, J=5.5 Hz, 1H), 8.10 (d, J=8.3 Hz,2H), 7.79 (app q, J=7.9 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.36-7.30 (m,1H), 7.21 (app dt, J=2.4, 8.5 Hz, 1H), 6.73 (s, 1H), 5.43 (s, 2H), 3.68(app t, J=5.9 Hz, 2H), 3.52-3.49 (m, 2H), 2.03 (s, 3H). ES-HRMS m/z493.0597 (M+H C₂₂H₁₉BrF₂N₂O₄ requires 493.0569).

Examples 233-243

By following the method of Example 232 and substituting ethanolamine forthe appropriate amine, the compounds of Examples 233-243 are prepared.The deprotection of the protected intermediates was accomplished with 4NHCl in dioxane to afford the compounds as hydrochloride salts.

Compound % M + H ESHRMS No. R₁ R₂ Yield MF Requires m/z Ex. 233CH₂CH₂NH— CH₂CH₂NH— 40.3 C₂₄H₂₂BrF₂N₃O₃ 518.0885 518.0866 Ex. 234 HCH₂CH₂NH₂ 57.1 C₂₂H₂₀BrF₂N₃O₃ 492.0729 492.0748 Ex. 235 H CH₂CH₂CH₂NH₂21.5 C₂₃H₂₂BrF₂N₃O₃ 506.0885 506.0915 Ex. 236 H OH 33.9 C₂₀H₁₅BrF₂N₂O₄465.0256 465.0259 Ex. 237 H CH₃ 20.7 C₂₁H₁₇BrF₂N₂O₃ 463.0463 463.0479Ex. 238 CH₃ CH₃ 22.3 C₂₂H₁₉BrF₂N₂O₃ 477.0620 477.0643 Ex. 239 CH₂CH₂O—CH₂CH₂O— 84.4 C₂₄H₂₁BrF₂N₂O₄ 519.0726 519.0723 Ex. 240 CH₂CH₂OH CH₂CH₂OH46.6 C₂₄H₂₃BrF₂N₂O₅ 537.0831 537.0854 Ex. 241 CH₂CH₂CH₂— CH₂CH₂CH₂— 76.5C₂₅H₂₃BrF₂N₂O₃ 517.0933 517.0892 Ex. 242 H CH(CH₃)₂ 52.6 C₂₃H₂₁BrF₂N₂O₃491.0776 491.0781 Ex. 243 CH₂CH₂— CH₂CH₂— 47.2 C₂₄H₂₁BrF₂N₂O₄ 503.0776503.0791

Ex. 2444-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide

Preparation of4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide.EXAMPLE 203 (0.500 g, 1.11 mmol) was suspended in tetrahydrofuran (5.0mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.234 g, 1.33 mmol) wasadded followed by 4-methylmorpholine (0.366 mL, 3.33 mmol). Theresulting mixture was stirred at room temperature for 1.5 hours at whichtime NH₄OH (2.5 mL) was added. The resulting mixture was stirred at roomtemperature overnight. H₂O (25 mL) and tetrahydrofuran (25 mL) wasadded. The aqueous layer was further extracted with ethyl acetate (25mL). The combined organic layers were washed with saturated sodiumcarbonate solution (25 mL), 1N HCl (25 mL), brine (25 mL), dried overNa₂SO₄, filtered and concentrated to provide a pale yellow solid (0.500g, 100%). ¹H NMR (400 MHz, DMF-d₆) δ 8.13 (s, 1H), 8.02 (d, J=8.5 Hz,2H), 7.70 (app q, J=7.9 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.41-7.34 (m,1H), 7.22 (app dt, J 1.8, 8.5 Hz, 1H), 6.71 (s, 1H), 5.37 (s, 2H), 1.97(s, 3H). ES-HRMS m/z 449.0281 (M+H C₂₀H₁₅BrF₂N₂O₃ requires 449.0307).

Ex. 2454-(Benzyloxy)-3-bromo-1-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one

Preparation of4-(Benzyloxy)-3-bromo-1-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H)-one.To a reaction vessel (borosilicate culture tube) was added EXAMPLE 197(0.100 g, 0.250 mmol) which was dissolved in N,N-dimethylformamide (2.0mL). 1-Hydroxybenzotriazole (0.017 g, 0.125 mmol) was added to thereaction vessel followed by approximately 0.423 g of the polymer boundcarbodiimide resin (1.8 mmol/g). Additional N,N-dimethylformamide (2 mL)was then added to the reaction vessel. The parallel reaction apparatuswas then orbitally shaken (Labline Benchtop Orbital Shaker) atapproximately 200 RPM at room temperature for 15 minutes. Morpholine(0.033 g, 0.0.375 mmol) dissolved in N,N-dimethlyformamide (0.5 mL) wasthen added to the reaction vessel and the reaction apparatus wasorbitally shaken at room temperature overnight. At this time thereaction was diluted with N,N-dimethylformamide (2.0 mL) anddichloromethane (4.0 mL) and treated with approximately 0.770 g ofpolyamine resin (2.63 mmol/g) and approximately 1.0 g ofmethylisocyanate functionalized polystyrene (1.10 mmol/g) and theorbital shaking was continued at 200 RPM at room temperature for 3hours. The reaction vessel was then opened and the solution phaseproduct was separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partially evaporation theinsoluble byproducts were rinsed with dichloromethane (2×10 mL). Thefiltrate was evaporated by blowing N₂ over the vial while heating (60°C.) in a reaction block (KEM-Lab Parallel Reactor) to give an off-whitesolid (0.092 g, 79%).

¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.5 Hz, 2H), 7.48-7.33 (m, 7H),7.27 (d, J=7.8 Hz, 1H), 6.19 (d, J=7.8 Hz, 1H), 5.29 (s, 2H), 3.76-3.47(br m, 8H). ES-HRMS m/z 469.0733 (M+H C₂₃H₂₁BrN₂O₄ requires 469.0757).

Ex. 2464-(Benzyloxy)-3-bromo-1-[4-(piperazin-1-ylcarbonyl)phenyl]pyridin-2(1H)-onehydrochloride

Preparation of4-(benzyloxy)-3-bromo-1-[4-(piperazin-1-ylcarbonyl)phenyl]pyridin-2(1H)-onehydrochloride. By following the method of Ex. 245 and substitutingN-tert-butyl carboxylate piperazine (0.070 g, 0.375 mmol) for morpholinethe title compound was prepared as the N-t-butoxycarbonyl protectedcompound. The deprotection of the N-t-butoxycarbonyl intermediate wasaccomplished with 4N HCl in dioxane to afford the title compound as itshydrochloride salt (0.112 g, >100%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.55(br s, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.48-7.33(m, 7H), 6.57 (d, J=7.8 Hz, 1H), 5.38 (s, 2H), 3.79-3.36 (br m, 4H),3.30-3.14 (br s, 4H). ES-HRMS m/z 468.0940 (M+H C₂₃H₂₂BrN₃O₃ requires468.0917).

Ex. 2474-[4-(Benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]-N-hydroxybenzamide

Preparation of4-[4-(Benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]-N-hydroxybenzamide. Byfollowing the method of EXAMPLE 245 and substitutingO-(tetrahydro-2H-pyranyl-2-yl)hydroxylamine (0.044 g, 0.375 mmol) formorpholine the title compound was prepared as the tetrahydropyranlyprotected compound. The deprotection of the tetrahydropyranlyintermediate was accomplished with 4N HCl in dioxane to afford the titlecompound (0.056 g, >71%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (br s, 1H),7.83 (d, J=8.6 Hz, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.48 7.35 (m, 7H), 6.55(d, J=7.8 Hz, 1H), 5.37 (s, 2H). ES-HRMS m/z 415.0278 (M+H C₁₉H₁₅BrN₂O₄requires 415.0288).

Ex. 248Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate

Step 1. Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpridin-2(1H)-one

(5.00 g, 19.90 mmol) was suspended in 1,2-dichloroethane (100 mL).Dichloroacetic acid (0.082 mL, 0.995 mmol) was added, followed byN-chlorosuccinimide (3.19 g, 23.88 mmol). The reaction mixture washeated at 80° C. for 15.5 hours. The 1,2-dichloroethane was evaporatedand the remaining solids were washed with acetonitrile to provide a tansolid (4.97 g, 88%).

Step 2. Preparation ofmethyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate.3-Chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpridin-2(1H)-one (Step 1)(4.97 g, 17.40 mmol) suspended in tetrahydrofuran (50 mL) was cooled inan ice-bath. Methyl 4-(bromomethyl)benzoate (5.98 g, 26.10 mmol) wasadded, followed by sodium hydride (0.835 g, 20.88 mmol, 60% dispersionin mineral oil). Once the addition was complete the cooling bath wasremoved in the mixture was heated to 50° C. for 19 hours. After coolingto room temperature saturated NH₄Cl (50 mL) was added. Ethyl acetate wasadded and the precipitate was collected by filtration. The filtrate wasfurther extracted with ethyl acetate. The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and evaporated.The resulting solid was combined with the precipitate and washed withhot ethyl acetate to give an off-white solid (5.24 g, 69%). ¹H NMR (400MHz, DMSO-d₆) δ 7.90 (d, J=8.5 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31(app dt, J=2.4, 9.9 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.17-7.13 (m, 1H),6.60 (s, 1H), 5.36 (s, 2H), 5.27 (s, 2H), 3.81 (s, 3H), 2.27 (s, 3H).ES-HRMS m/z 434.0931 (M+H C₂₂H₁₈BrF₂NO₄ requires 434.0965).

Example 249

3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-methylbenzamide

To a reaction vessel (borosilicate culture tube) was added EXAMPLE 169(0.300 g, 0.646 mmol). A stock solution of 1-hydroxybenzotriazole inN,N-dimethylformamide (3 mL, 0.11 M) was added followed by approximately1.10 g of the polymer bound carbodiimide resin (1.8 mmol/g). AdditionalN,N-dimethylformamide (2 mL) was then added to the reaction vessel. Theparallel reaction apparatus was then orbitally shaken (Labline BenchtopOrbital Shaker) at approximately 200 RPM at room temperature for 15minutes. N-Methylamine (0.50 mL, 0.999 mmol) was then added to thereaction vessel and the reaction apparatus was orbitally shaken at roomtemperature overnight. At this time the reaction was diluted withtetrahydrofuran (35 mL) and treated with approximately 2.0 g ofpolyamine resin (2.63 mmol/g) and approximately 2.6 g ofmethylisocyanate functionalized polystyrene (1.50 mmol/g) and theorbital shaking was continued at 200 RPM at room temperature for 4hours. The reaction vessel was then opened and the solution phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partial evaporation theinsoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). Thefiltrate was evaporated by blowing N₂ over the vial while heating (60°C.) in a reaction block (KEM-Lab Parallel Reactor) Chromatography (C-18,acetonitrile/H₂O with 0.1% trifluoroacetic acid) afforded a white solid(0.178 g, 58%). ¹H NMR (400 MHz, DMF-d₆) δ 7.65-7.53 (m, 3H), 7.37-7.28(m, 2H), 6.97-6.82 (m, 2H), 6.00 (s, 1H), 5.36 (s, 2H), 5.19 (s, 3H),2.96 (t, J=4.83 Hz, 3H), 2.29 (s, 3H). ES-HRMS m/z 477.0635 (M+HC₂₂H₁₉BrF₂N₂O₃ requires 477.0620).

Preparation of Examples 250-261

By following the method of Example 249 and replacing N-methylamine withthe appropriate amine, the compounds of Examples 250-261 are prepared.The deprotection of the protected intermediates was accomplished with 4NHCl in dioxane to afford the compounds as hydrochloride salts.

Compound % M + H ES-HRMS No. R₁ R₂ Yield MF Requires m/z Ex. 250CH₂CH₂NH— CH₂CH₂NH— 89 C₂₅H₂₄BrF₂N₃O₄ 532.1042 532.1067 Ex. 251 HCH₂CH₂NH₂ 75 C₂₃H₂₂BrF₂N₃O₃ 506.0885 506.0900 Ex. 252 H CH₂CH₂CH₂NH₂ 84C₂₄H₂₄BrF₂N₃O₃ 520.1042 520.1000 Ex. 253 H OH 45 C₂₁H₁₇BrF₂N₂O₄ 479.0413479.0394 Ex. 254 CH₃ CH₃ 69 C₂₃H₂₁BrF₂N₂O₃ 491.0776 491.0731 Ex. 255 HCH₃ 58 C₂₂H₁₉BrF₂N₂O₃ 479.0602 479.0598 Ex. 256 CH₂CH₂O— CH₂CH₂O— 69C₂₅H₂₃BrF₂N₂O₄ 533.0882 533.0857 Ex. 257 H CH₂CH₂OH 51 C₂₃H₂₁BrF₂N₂O₄507.0726 507.0698 Ex. 258 CH₂CH₂OH CH₂CH₂OH 25 C₂₅H₂₅BrF₂N₂O₅ 551.0988551.0972 Ex. 259 CH₂CH₂CH₂— CH₂CH₂CH₂— 62 C₂₆H₂₅BrF₂N₂O₃ 531.1089531.1088 Ex. 260 H CH(CH₃)₂ 46 C₂₄H₂₃BrF₂N₂O₃ 505.0933 505.0918 Ex. 261CH₂CH₂— CH₂CH₂— 60 C₂₅H₂₃BrF₂N₂O₃ 517.0933 517.0950

Example 262

N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-2-methoxyacetamide

To a reaction vessel (borosilicate culture tube) was added methoxyaceticacid (0.09 g, 1.00 mmol). A stock solution of 1-hydroxybenzotriazole (3mL, 0.16 M) and N-methylmorpholine (3 mL, 0.43 M) inN,N-dimethylformamide were added to the reaction vessel followed byapproximately 0.97 g of the polymer bound carbodiimide resin (1.38mmol/g). Additional N,N-dimethylformamide (3 mL) was then added to thereaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 4 hours.1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(EXAMPLE 161) (0.30 g, 0.668 mmol) was then added to the reaction vesselfollowed by additional N,N-dimethylformamide (5.0 mL) and the reactionapparatus was orbitally shaken at room temperature overnight. At thistime the reaction was diluted with tetrahydrofuran (20 mL) and treatedwith approximately 2.06 g of polyamine resin (2.63 mmol/g) andapproximately 2.67 g of methylisocyanate functionalized polystyrene(1.10 mmol/g) and the orbital shaking was continued at 200 RPM at roomtemperature for 4 hours. The reaction vessel was then opened and thesolution phase products were separated from the insoluble quenchedbyproducts by filtration and collection into a vial. After partialevaporation the insoluble byproducts were rinsed with tetrahydrofuran(2×10 mL). The filtrate was evaporated by blowing N₂ over the vial whileheating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) affordeda tan solid (0.321 g, 89.4%). ¹H NMR (400 MHz, DMF-d₆) δ 8.33 (br s,1H), 7.81 (app q, J=7-85 Hz, 1H), 7.40-7.23 (m, 5H), 7.09 (d, J=7.25 Hz,1H), 6.68 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, J=6.24 Hz, 2H),3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m/z 521.0891 (M+HC₂₄H₂₃BrF₂N₂O₄ requires 521.0882).

Preparation of Example 263-265

By following the method of Example 262 and replacing methoxyacetic acidwith the appropriate acid, the compounds of Examples 263-265 areprepared. The deprotection of the protected intermediates wasaccomplished with 4N HCl in dioxane to afford the compounds ashydrochloride salts.

Compound % M + H ES-HRMS No. R Yield MF Requires m/z Ex. 263 CH₂NH₂ 46.1C₂₃H₂₃BrF₂N₃O₃ 506.0885 506.0870 Ex. 264 CH₂NHCOCH₃ 70.4 C₂₅H₂₄BrF₂N₃O₄548.0991 548.1007 Ex. 265 CH₂OCOCH₃ 42.7 C₂₃H₂₁BrF₂N₂O₄ 549.0831549.0837

Example 266

N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-2-hydroxy-2-methylpropanamide

1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(EXAMPLE 161) (0.300 g, 0.668 mmol), 1-hydroxyisobutyric acid (0.215 g,2.064 mmol), 1-hydroxybenzotriazole (0.112 g, 0.826 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.185 g,0.963 mmol) were dissolved in N,N-dimethylacetamide (3 mL).N-methylmorpholine (0.209 g, 2.064 mmol) was added, and the reactionstirred for 1 hour at room temperature. The reaction was diluted withH₂O (50 mL) and the aqueous layer extracted with ethyl acetate (3×25mL). The combined organics were then washed with 1N HCl (25 mL),saturated Na₂CO₃ (25 mL), brine (25 mL), dried over Na₂SO₄, andconcentrated to yield an off-white solid (0.235 g, 64%). ¹H NMR (400MHz, DMF-d₆) δ 8.25 (br s, 1H), 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.21(m, 5H), 7.09 (d, J=6.84 Hz, 1H), 6.67 (s, 1H), 5.46 (s, 2H), 5.42 (s,2H), 4.42 (d, J=6.24 Hz, 2H), 2.44 (s, 3H), 1.38 (s, 6H). ES-HRMS m/z535.1024 (M+H C₂₅H₂₅BrF₂N₂O₄ requires 535.1039).

Example 267

N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-1-hydroxycyclopropanecarboxamide

By following the method of Example 266 and substituting1-hydroxy-1-cyclopropane-carboxylic acid for 1-hydroxyisobutyric acid,the title compound was prepared (0.352 g, 96%). ¹H NMR (400 MHz, DMF-d₆)δ 8.46 (app t, J=6.24 Hz, 1H), 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.22(m, 5H), 7.06 (d, J=7.05 Hz, 1H), 6.67 (s, 1H), 5.45 (s, 2H), 5.42 (s,2H), 4.46 (d, J=6.44 Hz, 2H), 2.45 (s, 3H), 1.17-1.12 (m, 2H), 0.93 (appq, J=3.82 Hz, 2H). ES-HRMS m/z 533.0861 (M+H C₂₅H₂₃BrF₂N₂O₄ requires533.0882).

Example 267

N′-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N,N-dimethylureaStep 1: Preparation of 4-nitrophenyl3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate

1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(EXAMPLE 161) (2.00 g, 4.45 mmol) was suspended in dichloromethane (15mL). Pyridine was added (0.43 mL, 5.34 mmol). After stirring for 10minutes at room temperature, a stock solution of 4-nitrophenylchloroformate (10.0 mL, 0.50 M) in dichloromethane was added dropwise.After stirring for 4.5 hours at room temperature, a stock solution of4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane wasagain added dropwise and stirring continued at 40° C. overnight. Thereaction mixture was concentrated and subjected to chromatography(silica gel, ethyl acetate with 10% methanol/hexanes) to afford a yellowsolid (1.11 g, 66%). ¹H NMR (400 MHz, DMSO d₆) δ 8.56 (app t, J=6.10 Hz,1H), 8.24-8.21 (m, 2H), 7.62 (app q, J=7.88 Hz, 1H), 7.40-7.27 (m, 7H),6.98 (d, J=7.52 Hz, 1H), 6.54 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.25(d, J=6.18 Hz, 2H), 2.30 (s, 3H). ES-HRMS m/z 614.0753 (M+HC₂₈H₂₂BrF₂N₃O₆ requires 614.0733).

Step 2: Preparation ofN′-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N,N-dimethylurea.To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate(from step 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0mL). The parallel reaction apparatus was then orbitally shaken (LablineBenchtop Orbital Shaker) at approximately 200 RPM at room temperaturefor 15 minutes. A stock solution of N,N-dimethylamine intetrahydrorfuran (0.427 mL, 2.0 M) was then added to the reaction vesseland the reaction apparatus was orbitally shaken at room temperatureovernight. The reaction mixture was concentrated and subjected tochromatography (silica gel, ethyl acetate with 10% methanol/hexanes)which afforded an off white solid (0.226 g, 63.3%). ¹H NMR (400 MHz,DMF-d₆) δ 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d,J=7.45 Hz, 1H), 6.88 (app t, J=5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H),5.42 (s, 1H), 4.35 (d, J=5.84 Hz, 1H), 2.92 (s, 6H), 2.44 (s, 3H).ES-HRMS m/z 520.1065 (M+H C₂₄H₂₄BrF₂N₃O₃ requires 520.1042).

Preparation of Example 268-270

By following the method of Example 267 and replacing N,N-dimethylaminewith the appropriate amine, the compounds of Examples 268-270 areprepared. The deprotection of the protected intermediates wasaccomplished with 4N HCl in dioxane to afford the compounds ashydrochloride salts.

Compound % M + H ES-HRMS No. R₁ R₂ Yield MF Requires m/z Ex. 268CH₂CH₂N— CH₂CH₂N— 66.6 C₂₆H₂₇BrF₂N₄O₃ 561.1307 561.1309 Ex. 269 H CH₃27.0 C₂₃H₂₂BrF₂N₃O₃ 506.0885 506.0898 Ex. 270 CH₂CH₂O— CH₂CH₂O— 64.4C₂₆H₂₆BrF₂N₃O₄ 562.1148 562.1137

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoicacid Step 1: Preparation of methyl3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and4-hydroxy-6-methyl-2-pyrone (62.57 g, 496.13 mmol) were suspended in1,2-dichlorobenzene (150 mL) and heated to 165° C. for 15 minutes. Thereaction was cooled to room temperature and extracted with 0.54M K₂CO₃(4×250 mL). The aqueous layers were acidified (pH 2) with 4N HCl. Theprecipitate was collected by filtration to afford a yellow-orange solid(20.24 g, 16%). The resulting filtrate was extracted with ethyl acetate(3×1 L). The organic layers were washed with brine (500 mL), dried overMgSO₄ and evaporated. The resulting solid was washed with hot H₂O toafford a yellow-orange solid (3.84 g, 3%). The two solids were thencombined. ¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (dt, J=1.31, 7.79 Hz, 1H),7.69 (app t, J=1.78 Hz, 1H), 7.62 (t, J=7.78 Hz, 1H) 7.49 (ddd, J=1.07,1.07, 7.85 Hz, 1H), 5.89 (dd, J=087, 2.48 Hz, 1H), 5.55 (app d, J=0.94Hz, 1H), 3.83 (s, 3H), 1.80 (s, 3H). ES-HRMS m/z 260.0895 (M+H C₁₄H₁₃NO₄requires 260.0917).

Step 2: Preparation of methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate from step 1)(24.00 g, 92.57 mmol) and K₂CO₃ (15.35 g, 111.08 mmol) were dissolved inN,N-dimethylformamide (220 mL). 2,4-Difluorobenzyl bromide (20.12 g,97.20 mmol) was then added and the reaction mixture stirred for 48 hoursat room temperature. The reaction mixture was diluted with H₂O (1 L) andthe precipitate collected by filtration to afford a white solid (4.08 g,11%). The resulting oil was purified by chromatography (silica gel,ethyl acetate with 10% methanol/hexanes) to afford an off white solid(11.88 g, 33%). The two solids were combined. ¹H NMR (400 MHz, CDl₃) δ8.11 (dt, J=1.41, 7.79 Hz, 1H), 7.87 (app t, J=1.78 Hz, 1H), 7.58 (appt, J=7.69 Hz, 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, J=2.68Hz, 1H), 5.90 (ddd, J=0.94, 1.74, 1.74 Hz, 1H), 5.97 (s, 1H), 3.90 (s,3H), 1.89 (s, 3H). ES-HRMS m/z 386.1179 (M+H C₂₁H₁₇F₂NO₄ requires386.1198).

Step 3: Preparation of methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(from step 2) (15.85 g, 41.130 mmol) suspended in acetonitrile (165 mL)was cooled in an ice-bath. N-bromosuccinimide (7.687 g, 43.186 mmol) wasadded and the ice-bath was removed. The reaction mixture was stirred for1.5 hours at room temperature. Reaction was concentrated and subjectedto chromatography (silica gel, ethyl acetate with 10% methanol/hexanes)afforded an off white solid (17.63 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ8.17 (dt, J=1.41, 7.85 Hz, 1H), 7.90 (t, J=1.81 Hz, 1H), 7.67-7.41 (m,3H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01(s, 3H). ES-HRMS m/z 464.0286 (M+H C₂₁H₁₆BrF₂NO₄ requires 464.0304).

Step 4: Preparation of the title compound. Methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(from step 3) (10.0 g, 21.539 mmol) was dissolved in methanol (36 mL)and tetrahydrofuran (14 mL). 4N NaOH (13.5 mL, 53.847 mmol) was added.The resulting mixture was stirred for 1.5 hours at room temperature. Thereaction was acidified (pH 2) with 4N HCl. The precipitate was collectedby filtration to afford an off white solid (7.83 g, 81%) ¹H NMR (400MHz, DMSO-d₆) δ 8.01 (dt, J=1.41, 7.65 Hz, 1H), 7.76 (app t, J=1.78 Hz,1H), 7.76-7.15 (m, 5H), 6.66 (s, 1H), 5.32 (s, 2H), 1.92 (s, 3H).ES-HRMS m/z 450.0134 (M+H C₂₀H₁₄BrF₂NO₄ requires 450.0147).

Example 272

Ethyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

By following the method of Example 271 and substituting ethyl3-aminobenzoate for methyl 3-aminobenzoate, the title compound wasprepared (2.66 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ 8.13 (dt, J=1.41, 7.85Hz, 1H), 7.84 (t, J=1.88 Hz, 1H), 7.62-7.55 (m, 2H), 7.36 (app dq,J=1.07, 7.85 Hz, 1H), 6.96 (app dt, J=2.55, 8.35 Hz, 1H), 6.88-6.84 (m,1H), 6.08 (s, 1H), 5.25 (s, 2H), 4.42-4.30 (m, 2H), 1.96 (s, 3H), 1.36(t, J=7.12 Hz, 3H). ES-HRMS m/z 478.0482 (M+H C₂₂H₁₈BrF₂NO₄ requires478.0460).

Example 273

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl2-oxopyridin-1(2H)-yl]-N-methylbenzamide

To a reaction vessel (borosilicate culture tube) was added EXAMPLE271-(0.300 g, 0.666 mmol). A stock solution of 1-hydroxybenzotriazole inN,N-dimethylformamide (3 mL, 0.11 M) was added to the reaction vesselfollowed by approximately 0.97 g of the polymer bound carbodiimide resin(1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added tothe reaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. N-Methylamine in tetrahydrofuran (0.50mL, 0.999 mmol) was then added to the reaction vessel and the reactionapparatus was orbitally shaken at room temperature overnight. At thistime the reaction was diluted with tetrahydrofuran (30 mL) and treatedwith approximately 2.0 g of polyamine resin (2.63 mmol/g) andapproximately 3.6 g of methylisocyanate functionalized polystyrene (1.10mmol/g) and the orbital shaking was continued at 200 RPM at roomtemperature for 4 hours. The reaction vessel was then opened and thesolution phase products were separated from the insoluble quenchedbyproducts by filtration and collection into a vial. After partialevaporation the insoluble byproducts were rinsed with tetrahydrofuran(2×10 mL). The filtrate was evaporated by blowing N₂ over the vial whileheating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) to givean off-white solid (0.189 g, 61%). ¹H NMR (400 MHz, DMF-d₆) δ 8.56 (brd, J=4.16 Hz, 1H), 8.05-7.76 (m, 3H), 7.66 (t, J=7.79 Hz, 1H), 7.56-7.19(m, 3H), 6.74 (s, 1H), 5.43 (s, 2H), 3.46 (s, 3H), 2.03 (s, 3H). ES-HRMSm/z 463.0476 (M+H C₂₁H₁₇BrF₂N₂O₃ requires 463.0463).

Preparation of Example 274-289

By following the method of Example 273 and replacing N-methylamine withthe appropriate amine, the compounds of Examples 274-289 are prepared.The deprotection of the protected intermediates was accomplished with 4NHCl in dioxane to afford the compounds as their hydrochloride salts.

Compound % M + H ES-HRMS No. R1 R2 Yield MF Requires m/z Ex. 274CH2CH2NH— CH2CH2NH— 92.8 C₂₄H₂₂BrF₂N₂O₃ 518.0885 518.0865 Ex. 275 HCH2CH2NH2 95.7 C₂₂H₂₀BrF₂N₃O₃ 492.0729 492.0711 Ex. 276 H CH2CH2CH2NH297.8 C₂₃H₂₂BrF₂N₃O₃ 506.0885 506.0889 Ex. 277 H OH 91.0 C₂₀H₁₅BrF₂N₂O₄465.0256 465.0278 Ex. 278 CH3 CH3 67.7 C₂₂H₁₉BrF₂N₂O₂ 477.0620 477.0626Ex. 279 CH2CH2O— CH2CH2O— 86.7 C₂₄H₂₁BrF₂N₂O₄ 519.0726 519.0696 Ex. 280H CH2CH2OH 78.3 C₂₂H₁₉BrF₂N₂O₄ 493.0569 493.0575 Ex. 281 CH2CH2CH2—CH2CH2CH2— 87.9 C₂₅H₂₃BrF₂N₂O₃ 517.0933 517.0918 Ex. 282 H CH(CH3)2 80.6C₂₃H₂₁BrF₂N₂O₃ 491.0776 491.0797 Ex. 283 CH2CH2— CH2CH2— 87.9C₂₄H₂₁BrF₂N₂O₄ 503.0776 503.0732 Ex. 284 CH2CH2N(CH3)— CH2CH2N(CH3)—75.8 C₂₅H₂₄BrF₂N₃O₃ 532.1042 532.1038 Ex. 285 H CH2CH2N(CH3)2 86.1C₂₄H₂₄BrF₂N₃O₃ 520.1042 520.1030 Ex. 286 H CH2CH2OCH3 90.2C₂₃H₂₁BrF₂N₂O₄ 507.0726 507.0680 Ex. 287 CH3 CH2CH2N(CH3)2 60.0C₂₅H₂₆BrF₂N₃O₃ 534.1198 534.1155 Ex. 288 CH3 CH2CH2OH 81.6C₂₃H₂₁BrF₂N₂O₄ 507.0726 507.0694 Ex. 289 CH3 CH2CH2OCH3 94.4C₂₄H₂₃BrF₂N₂O₄ 521.0882 521.0862

Example 290

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide

EXAMPLE 271-(2.00 g, 4.44 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (0.94 g, 5.33 mmol) were suspendedin tetrahydrofuran (20 mL). 4-Methylmorpholine (1.5 mL, 13.32 mmol) wasadded. The resulting mixture was stirred for 1.5 hours at roomtemperature. NH₄OH (10 mL, 148.00 mmol) was added and the reaction wasstirred for 0.5 hours at room temperature. H₂O (50 mL) andtetrahydrofuran (50 mL) were added and the organic layer was separated.The aqueous phase was extracted with ethyl acetate (75 mL) and thecombined organics were washed with saturated Na₂CO₃ (50 mL), 1N HCl (50mL), and brine (50 mL). The organic phase was dried over Na₂SO₄ andevaporated. The resulting solid was washed with diethyl ether to give awhite solid (1.86 g, 93%). ¹H NMR (400 MHz, DMF-d₆) δ 8.20 (br s, 1H),8.10-8.07 (m, 1H), 7.79 (s, 1H), 7.79 (app q, J=7.83 Hz, 1H), 7.66 (appt, J=7.79 Hz, 1H), 7.57-7.54 (m, 1H), 7.46 (br s, 1H), 7.36-7.19 (m,2H), 6.74 (s, 1H), 5.43 (s, 2H), 2.04 (s, 3H). ES-HRMS m/z 449.0307 (M+HC₂₀H₁₅BrF₂N₂O₃ requires 449.0307).

Example 291

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoicacid Step 1: Preparation of methyl3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

The product from step 2, Example 271-(4.54 g, 11.78 mmol) andN-chlorosuccinimide (1.65 g, 12.37 mmol) were suspended indichloromethane (12 mL). Dichloroacetic acid (0.10 ml, 1.22 mmol) wasadded and the reaction mixture was stirred overnight at 40° C. Thereaction was cooled to room temperature and a precipitate formed. Theprecipitate was collected by filtration and washed with dichloromethane(3×10 mL) to afford a white solid (1.75 g, 35%). The filtrate wasconcentrated and subjected to chromatography (silica gel, ethyl acetatewith 10% methanol/hexanes) to afforded an off white solid (1.29 g, 26%).The two solids were then combined. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (dt,J=1.38, 7.83 Hz, 1H), 7.85 (t, J=1.74 Hz, 1H), 7.60-7.52 (m, 2H), 7.37(dq, J=0.92, 7.92 Hz, 2H), 6.95 (app dt, J=2.55, 8.32 Hz, 1H), 6.89-6.83(m, 1H), 6.11 (s, 1H), 5.24 (s, 2H), 3.90 (s, 3H), 1.96 (s, 3H). ES-HRMSm/z 420.0783 (M+H C₂₁H₁₆ClF₂NO₄ requires 420.0809).

Step 2: Methyl3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(from step 1) (2.90 g, 6.91 mmol) was dissolved in methanol (5 mL) andtetrahydrofuran (12 mL). 4N NaOH (4.3 mL, 17.27 mmol) was added. Theresulting mixture was stirred for 1.5 hours at room temperature. Thereaction was acidified (pH-2) with 4N HCl. The precipitate was collectedby filtration to afford an off white solid (2.36 g, 84%). ¹H NMR (400MHz, DMSO-d₆) δ 8.01 (dt, J=1.441, 7.65 Hz, 1H), 7.76 (app t, J=1.68 Hz,1H), 7.69-7.53 (m, 3H), 7.36-7.14 (m, 2H), 6.69 (s, 1H), 5.32 (s, 2H),1.93 (s, 3H). ES-HRMS m/z 406.0662 (M+H C₂₀H₁₄ClF₂NO₄ requires406.0652).

Example 292

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one

The starting material (0.550 g, 1.540 mmol) and N-chlorosuccinimide(0.214 g, 1.602 mmol) were suspended in dichloromethane (15 mL).Dichloroacetic acid (0.01 ml, 0.154 mmol) was added and the reactionmixture heated to 40° C. for 9 hours. The reaction was cooled to roomtemperature and a precipitate formed. The precipitate was collected byfiltration and washed with dichloromethane (3×10 mL) to afford a whitesolid (0.286 g, 47%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (app q, J=7.35Hz, 1H), 7.30-7.24 (m, 2H), 7.00 (br s, 1H), 6.85 (app dt, J=2.37, 6.24Hz, 1H), 6.82-6.67 (m, 2H), 6.01 (s, 1H), 5.07 (s, 2H), 4.48 (d, J=5.24Hz, 2H), 1.81 (app d, J=0.40 Hz, 3H). ES-HRMS m/z 392.0885 (M+HC₂₀H₁₆ClF₂NO₃ requires 392.0860).

Example 293

1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1: Preparation of1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

2,4,6-Trichloro-[1,3,5]-triazine (3.09 g, 16.78 mmol) was dissolved inN,N-dimethylformamide (45 mL). The reaction mixture was stirred at roomtemperature for 1 hour and then dichloromethane (90 mL) was added. Thealcohol (5.72 g, 15.99 mmol) was then added. The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith dichloromethane (200 mL) and the organic phase was washed with H₂O(200 mL), saturated Na₂CO₃ (200 mL), 1N HCl (200 mL), and brine (200mL). The organic phase was dried over MgSO₄ and evaporated to give anorange solid (5.95 g, 99%).

Step 2: Preparation of1-[3-(aminomethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onefrom step 1-(1.00 g, 2.66 mmol) was suspended in methanol (5 mL). Thesuspension was then brought to −78° C. and NH₃ was bubbled through thereaction mixture for 10 minutes. The reaction was then slowly allowed towarm to room temperature and stirred at room temperature for 4 days. Thereaction was concentrated and the residue taken up in CH₂Cl₂ andfiltered to remove excess salt. The filtrate was concentrated to afforda tan solid (0.94 g, 99%).

Step 3: Preparation of title compound.1-[3-(aminomethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onefrom step 3 (3.89 g, 10.93 mmol) suspended in acetonitrile (42 mL) wascooled in an ice-bath. N-bromosuccinimide (2.04 g, 11.47 mmol) was addedand the ice-bath was removed. The reaction mixture was stirred for 1.5hours at room temperature. The reaction was diluted with acetonitrile(100 mL) and the precipitate that formed was collected by filtration andwashed with acetonitrile (3×30 mL) to afford an off-white solid (2.74 g,58%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.67-7.59 (m, 3H), 7.34-7.31 (m, 2H),7.04 (app t, J=8.72 Hz, 2H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s,2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m/z 435.0538 (M+HC₂₀H₁₇BrF₂N₂O₂ requires 435.0514).

Example 294

N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}methanesulfonamide

To a reaction vessel (borosilicate culture tube) was added EXAMPLE 293(0.200 g, 0.459 mmol) and N,N-dimethylformamide (4 mL). A stock solutionof 4-methylmorpholine in N,N-dimethylformamide (1.8 mL, 1.0 M) was addedto the reaction vessel and the parallel reaction apparatus was thenorbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200RPM at room temperature for 10 minutes. A stock solution ofmethanesulfonyl chloride in N,N-dimethylformamide (4.50 mL, 0.15 M) wasthen added to the reaction vessel and the reaction apparatus wasorbitally shaken at room temperature for 2 hours. At this time thereaction was diluted with dichloromethane (4 mL) and treated withapproximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately0.8 g of methylisocyanate functionalized polystyrene (1.7 mmol/g) andthe orbital shaking was continued at 200 RPM at room temperatureovernight. The reaction vessel was then opened and the solution phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partial evaporation theinsoluble byproducts were rinsed with dichloromethane (2×5 mL). Thefiltrate was evaporated by blowing N₂ over the vial while heating (60°C.) in a reaction block (KEM-Lab Parallel Reactor) to give a yellowsolid (0.190 g, 81%). ¹H NMR (400 MHz, CD₃OD) δ 7.63 (app q, J=7.00 Hz,1H), 7.56-7.50 (m, 2H), 7.25 (m, 1H), 7.16 (dt, J=1.94, 7.25 Hz, 1H),7.04 (app t, J=8.59 Hz, 2H), 6.58 (s, 1H), 5.34 (s, 2H), 4.30 (s, 2H),2.87 (s, 3H), 2.03 (s, 3H). ES-HRMS m/z 513.0313 (M+H C₂₁H₁₉BrF₂N₂O₄Srequires 513.0290).

Preparation of Example 295-296

By following the method of Example 294 and replacing methanesulfonylchloride with the appropriate acid chloride, the compounds of Examples295-296 are prepared.

Compound % M + H ES-HRMS No. R Yield MF Requires m/z Ex. 295 CH₃ 78.0C₂₂H₁₉BrF₂N₂O₃ 477.0620 477.0640 Ex. 296 OCH₃ 84.0 C₂₂H₁₉BrF₂N₂O₄493.0569 493.0591

Example 297

N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-2-methoxyacetamide

To a reaction vessel (borosilicate culture tube) was added approximately2.87 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by astock solution of methoxyacetic acid (8.0 mL, 0.10 M) inN,N-dimethylacetamide. A stock solution of 1-hydroxybenzotriazole inN,N-dimethylacetamide (3.0 mL, 0.10 M) and N-methylmorpholine (6.0 mL,0.10 M) in 1,2-dichloroethane were added to the reaction vessel. Theparallel reaction apparatus was then orbitally shaken (Labline BenchtopOrbital Shaker) at approximately 200 RPM at room temperature for 4hours. A stock solution of EXAMPLE 293 in N,N-dimethylacetamide (5.0 mL,0.10 M) was then added to the reaction vessel and the reaction apparatuswas orbitally shaken at room temperature overnight. At this time thereaction was diluted with 1,2-dichloroethane (10 mL) and treated withapproximately 1.70 g of polyamine resin (2.63 mmol/g) and approximately0.84 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) andthe orbital shaking was continued at 200 RPM at room temperature for 4hours. The reaction vessel was then opened and the solution phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partial evaporation theinsoluble byproducts were rinsed with N,N-dimethylacetamide (2×5 mL).The filtrate was evaporated by blowing N₂ over the vial while heating(60° C.) in a reaction block (KEM-Lab Parallel Reactor) and subjected tochromatography (silica gel, ethyl acetate with 10% methanol/hexanes)afforded an off white solid (0.081 g, 28%). ¹H NMR (400 MHz, DMF-d₆) δ7.59 (q, J=7.65 Hz, 1H), 7.46 (app t, J=7.55 Hz, 1H), 7.40-7.37 (m, 1H),7.11-7.07 (m, 2H), 7.00 (t, J=8.56 Hz, 2H), 6.54 (s, 1H), 5.30 (s, 2H),4.43 (s, 2H), 3.88 (s, 2H), 3.35 (app d, J=0.80 Hz, 2H), 1.97 (s, 3H).ES-HRMS m/z 507.0699 (M+H C₂₃H₂₁BrF₂N₂O₄ requires 507.0726).

Preparation of Examples 298-300

By following the method of and replacing methoxyacetic acid with theappropriate acid, the compounds of Examples 298-300 are prepared. Thedeprotection of the protected intermediates was accomplished with 4N HClin dioxane or 1 M K₂CO₃ in methanol to afford the compounds ashydrochloride salts.

Compound % M + H ES-HRMS No. R. Yield MF Requires m/z Ex. 298 CH₂OCOCH₃35.5 C₂₄H₂₁BrF₂N₂O₅ 535.0675 535.0686 Ex. 299 CH₂NH₂ 32.6 C₂₂H₂₀BrF₂N₃O₃492.0729 492.0744 Ex. 300 CH₂OH 33.4 C₂₂H₁₉BrF₂N₂O₄ 493.0569 493.0578

Example 301

N′-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-N,N-dimethylureaStep 1: Preparation of 4-nitrophenyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate

1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(1.08 g, 2.48 mmol) was suspended in dichloromethane (7.5 mL). Pyridinewas added (0.222 mL, 2.74 mmol). After stirring for 10 minutes at roomtemperature, a stock solution of 4-nitrophenyl chloroformate (5.0 mL,0.50 M) in dichloromethane was added dropwise. After stirring for 4.5hours at room temperature, a stock solution of 4-nitrophenylchloroformate (2.5 mL, 0.50 M) in dichloromethane was again addeddropwise and stirring continued at room temperature overnight. Thereaction mixture was concentrated and subjected to chromatography(silica gel, ethyl acetate with 10% methanol/hexanes) afforded a yellowsolid (0.85 g, 57%).

Step 2: Preparation of title compound. To a reaction vessel(borosilicate culture tube) was added 4-nitrophenyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate(from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). Theparallel reaction apparatus was then orbitally shaken (Labline BenchtopOrbital Shaker) at approximately 200 RPM at room temperature for 15minutes. A stock solution of N,N-dimethylamine in tetrahydrorfuran (0.15mL, 2.0 M) was then added to the reaction vessel and the reactionapparatus was orbitally shaken at room temperature overnight. Thereaction mixture was concentrated and subjected to chromatography(silica gel, ethyl acetate with 10% methanol/hexanes) which afforded anoff white solid (0.065 g, 51%). ¹H NMR (400 MHz, DMF-d₆) δ 7.58 (app q,J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz,1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt,J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H),4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+HC₂₃H₂₂BrF₂N₃O₃ requires 506.0885).

Preparation of Examples 302-303

By following the method of Example 301 and substitutingN,N-dimethylamine with the appropriate amine, the compounds of Examples302-303 are prepared.

Compound % M + H ES-HRMS No. R₁ R₂ Yield MF Requires m/z Ex. 302 H CH₃52.3 C₂₂H₂₀BrF₂N₃O₃ 492.0729 492.0737 Ex. 303 CH₂CH₂O— CH₂CH₂O— 50.7C₂₅H₂₄BrF₂N₃O₄ 548.0991 548.0962

Example 304

N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}urea

To a reaction vessel (borosilicate culture tube) was added EXAMPLE 293(0.200 g, 0.459 mmol) and tetrahydrofuran (4.0 mL). A stock solution of4-methylmorpholine in tetrahydrofuran (1.8 mL, 1.0 M) was added to thereaction vessel and the parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 10 minutes. A stock solution of trimethylsilylisocyanate in tetrahydrofuran (4.0 mL, 0.2 M) was then added to thereaction vessel and the reaction apparatus was orbitally shaken at roomtemperature for two hours. At this time the reaction was diluted withtetrahydrofuran (4.0 mL) and the resulting precipitate collected byfiltration. The solid was then washed with tetrahydrofuran (3×5 mL) toafford a white solid (0.214 g, 97%). ¹H NMR (400 MHz, CD₃OD) δ 7.72 (appq, J=7.83 Hz, 1H), 7.55 (app t, J=8.06 Hz, 1H), 7.46 (d, J=7.52 Hz, 1H),7.25-7.14 (m, 4H), 6.65 (s, 1H), 5.65 (app t, J=0.80 Hz, 1H), 5.40 (s,2H), 4.38 (s, 2H), 2.05 (s, 3H). ES-HRMS m/z 478.0594 (M+HC₂₁H₁₈BrF₂N₃O₃ requires 478.0572),

Example 305

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{3-[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-{3-[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(1H)-one

1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(from step 1 of the synthesis of EXAMPLE 293) (0.500 g, 1.330 mmol) wassuspended in a stock solution of N,N-dimethylamine in methanol (2.0 mL,2.0 M) and stirred overnight at room temperature. Reaction wasconcentrated and the residue partitioned between H₂O (25 mL) and ethylacetate (25 mL). The aqueous layer was further extracted with ethylacetate (2×30 ml), and the combined organics were washed with brine (30mL), dried over MgSO₄, and concentrated to afford an off-white solid(0.508 g, 99%).

Step 2: Preparation of the title compound.4-[(2,4-difluorobenzyl)oxy]-1-{3-[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(1H)-onefrom step 1-(0.200 g, 0.521 mmol) was suspended in acetonitrile (2.5 mL)and cooled in an ice-bath. N-bromosuccinimide (0.097 g, 0.547 mmol) wasadded and the ice-bath was removed. The reaction mixture was stirred for1.5 hours at room temperature. The reaction was diluted withacetonitrile (100 mL). The precipitate that formed was collected byfiltration and washed with acetonitrile (3×15 mL) to afford a yellowsolid (0.160 g, 66%). Chromatography (C-18, acetonitrile/H₂O with 0.1%trifluoroacetic acid, followed by chromatography silica gel, ethylacetate with 10% methanol/hexanes) afforded an off-white solid (0.024 g,10%). ¹H NMR (400 MHz, CD₃OD) δ 7.68 (app q, J=7.85 Hz, 1H), 7.58 (appt, J=7.65 Hz, 1H), 7.50 (app d, J=7.85 Hz, 1H), 7.25-7.05 (m, 4H), 6.63(s, 1H), 5.39 (s, 2H), 3.61 (app q, J=12.08 Hz, 2H), 2.32 (s, 6H), 2.08(s, 3H). ES-HRMS m/z 463.0782 (M+H C₂₂H₂₁BrF₂N₂O₂ requires 463.0827).

Example 306

N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzyl}acetamide

1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-onehydrochloride (0.150 g, 0.389 mmol) was dissolved inN,N-dimethylformamide (3.5 mL). A stock solution of 4-methylmorpholinein N,N-dimethylformamide (1.5 mL, 1.0 M) was added and the reactionstirred at room temperature for 10 minutes. A stock solution of acetylchloride in N,N-dimethylformamide (3.0 mL, 0.2 M) was then added to thereaction vessel and the reaction apparatus was orbitally shaken at 200RPM for 2 hours at room temperature. At this time the reaction wasdiluted with dichloromethane (4 mL) and treated with approximately 1.8 gof polyamine resin (2.63 mmol/g) and approximately 0.8 g ofmethylisocyanate functionalized polystyrene (1.7 mmol/g) and the orbitalshaking was continued at 200 RPM at room temperature overnight. Thereaction vessel was then opened and the solution phase products wereseparated from the insoluble quenched byproducts by filtration andcollection into a vial. After partial evaporation the insolublebyproducts were further rinsed with dichloromethane (3×5 mL) andcombined with the partially concentrated filtrate. The resultingfiltrate was concentrated by blowing N₂ over the vial while heating (60°C.) in a reaction block (KEM-Lab Parallel Reactor) to give an off-whitesolid (0.083 g, 50%). ¹H NMR (400 MHz, CD₃OD) δ 7.59 (d, J=7.79 Hz, 1H),7.48-7.29 (m, 9H), 6.55 (d, J=7.79 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H),1.98 (s, 3H). ES-HRMS m/z 427.0625 (M+H C₂₁H₁₉BrN₂O₃ requires 427.0652).

Example 307

N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]benzyl}-2-hydroxyacetamide

To a reaction vessel (borosilicate culture tube) was added approximately1.95 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by astock solution of glycolic acid (5.8 mL, 0.10 M) inN,N-dimethylacetamide. A stock solution of 1-hydroxybenzotriazole inN,N-dimethylacetamide (0.4 mL, 0.10 M) and N-methylmorpholine in1,2-dichloroethane (3.9 mL, 0.10 M) were added to the reaction vessel.The parallel reaction apparatus was then orbitally shaken (LablineBenchtop Orbital Shaker) at approximately 200 RPM at room temperaturefor 2 hours. A stock solution of1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-onehydrochloride in N,N-dimethylacetamide (0.05 M, 7.8 mL) was then addedto the reaction vessel and the reaction apparatus was orbitally shakenat room temperature overnight. At this time the reaction was dilutedwith 1,2-dichloroethane (8 mL) and treated with approximately 1.17 g ofpolyamine resin (2.63 mmol/g) and approximately 0.58 g ofmethylisocyanate functionalized polystyrene (1.50 mmol/9) and theorbital shaking was continued at 200 RPM at room temperature for 4hours. The reaction vessel was then opened and the solution phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partial evaporation theinsoluble byproducts were rinsed with N,N-dimethylacetamide (2×5 mL) andcombined with the partially concentrated filtrate. The filtrate wasconcentrated by blowing N₂ over the vial while heating (60° C.) in areaction block (KEM-Lab Parallel Reactor) and subjected tochromatography (silica gel, ethyl acetate with 10% methanol/hexanes)which afforded an off white solid (0.081 g, 21%). ¹H NMR (400 MHz,CD₃OD) δ 7.55-7.30 (m, 10H), 6.51 (d, J=7.85 Hz, 1H), 5.37 (s, 2H), 4.52(s, 2H), 4.08 (s, 2H). ES-HRMS m/z 443.0605 (M+H C₂₁H₁₉BrN₂O₄ requires443.0601).

Example 308

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl1-(2-morpholin-4-ylethyl)pyridin-2(1H)-one

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.100 g,0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol) and4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended inacetonitrile (4 mL). The reaction was stirred at 60° C. overnight. H₂O(25 mL) was added and the resulting precipitate was collected byfiltration. The solid was subjected to chromatography (silica gel, ethylacetate with 10% methanol) afforded an off-white solid (0.040 g, 30%).¹H NMR (400 MHz, CDCl₃) δ 7.55 (app q, J=7.92 Hz, 1H), 6.93 (app t,J=8.39 Hz, 1H), 6.84 (app t, J=9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H),4.16 (app t, J=6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J=6.38 Hz, 2H),2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C₁₉H₂₁BrF₂N₂O₃requires 443.0776).

Example 309

ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanoate

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.50 g,1.78 mmol) and cesium fluoride (0.0027 g, 0.178 mmol) were suspended intetrahydrofuran (10 mL) followed by dropwise addition of tetraethylorthosilicate (0.37 g, 1.78 mmol) at room temperature. After stirring for 10minutes at room temperature, ethyl acrylate (0.23 g, 2.32 mmol) wasadded dropwise and the reaction stirred at room temperature overnight.The reaction mixture was filtered through a pad of Celite®. The filtratewas concentrated and the resulting residue subjected to chromatography(silica gel, ethyl acetate with 10% methanol/hexanes) to afford a whitesolid (0.62 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J=7.79 Hz, 1H),7.41-7.29 (m, 5H), 6.03 (d, J=7.65 Hz, 1H), 5.20 (s, 2H), 4.17 (t,J=5.98 Hz, 2H), 4.07 (q, J=7.16 Hz, 2H), 2.83 (t, J=5.98 Hz, 2H), 1.19(t, J=7.18 Hz, 3H) ES-HRMS In/z 380.0523 (M+H C₁₇H₁₈BrNO₄ requires380.0492).

Example 310

methyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H)-yl]propanoate

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (5.00 g,17.85 mmol) and cesium fluoride (0.27 g, 1.78 mmol) were suspended intetrahydrofuran (50 mL) followed by dropwise addition oftetramethylortho silicate (2.70 g, 17.85 mmol) at room temperature.After stirring for 10 minutes at room temperature, methyl acrylate (2.00g, 23.20 mmol) was added dropwise and the reaction stirred at roomtemperature for 48 hours. The reaction mixture was filtered through apad of Celite®. The filtrate was concentrated and the resulting residuesubjected to chromatography (silica gel, ethyl acetate with 10%methanol/hexanes) to afford a white solid (6.10 g, 93%). ¹H NMR (400MHz, CDCl₃) δ 7.42 (d, J=7.65 Hz, 1H), 7.41-7.29 (m, 5H), 6.04 (d,J=7.65 Hz, 1H), 5.20 (s, 2H), 4.17 (t, J=5.91 Hz, 2H), 3.63 (s, 3H),2.85 (t, J=5.91 Hz, 2H). ES-HRMS m/z 366.0350 (M+H C₁₆H₁₆BrNO₄ requires366.0335).

Example 311

N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-2,6-difluorobenzamideStep 1: Preparation of 3,4-dibromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (2.00 g, 4.65 mmol), KBr (5.53 g, 46.49 mmol),and 18-Crown-6-(0.10 g, 0.38 mmol) were dissolved inN,N-dimethylacetamide (26 mL). The reaction mixture was then heated atreflux for 16 hours. The reaction was concentrated and the resultingresidue was partition between water (50 mL) and ethyl acetate (3×50 mL).The combined organics were washed with H₂O (2×30 mL), brine (50 mL),dried over MgSO₄, concentrated, and subjected to chromatography (silicagel, ethyl acetate with 10% methanol/hexane) to afford a brown solid(0.850 g, 51%).

Step 2: Preparation of4-azido-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

Sodium azide (1.08 g, 16.62 mmol) was suspended in N,N-dimethylformamide(10 mL) and a stock solution of3,4-dibromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 1) inN,N-dimethylformamide (33.0 mL, 0.33 M) was added and the resultingmixture was heated to 60° C. for 4 hours. Ice water (30 mL) was addedand the aqueous layer was extracted with ethyl acetate (4×50 mL). Thecombined organics were washed with H₂O (3×50 mL), brine (2×25 mL), driedover MgSO₄, concentrated, and subjected to chromatography (silica gel,ethyl acetate with 10% methanol/hexane) to afford an off-white solid(3.50 g, 98%).

Step 3: Preparation of4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one hydrochloride

4-azido-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 2) (4.00g, 12.38 mmol) was suspended in ethyl acetate (300 mL) and Fe (2.07 g,37.14 mmol) was added. A stock solution of NH₄Cl in H₂O (300 mL, 0.2 M)was added and the reaction mixture was stirred at room temperature for36 hours. The reaction was filtered through a pad of Celite® andconcentrated. The resulting solid was dissolved in ethyl acetate (150mL) and washed with water (3×50 mL), brine (50 mL), dried over MgSO₄,and concentrated. ¹H NMR (400 MHz, CD₃OD) δ 7.38 7.29 (m, 2H), 7.05 (d,J=7.79 Hz, 1H), 6.99 (d, J=8.99 Hz, 2H), 6.03 (d, J=7.39 Hz 1H), 5.09(s, 2H). ES-HRMS m/z 297.0023 (M+H C₂₀H₁₇BrF₂N₂O₂ requires 297.0033).

Step 4: Preparation of the title compound.4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) weresuspended in acetonitrile (5 mL) followed by dropwise addition oftriethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for10 minutes at room temperature before being cooled to 0° C.2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise andthe reaction was heated at reflux overnight. The reaction was cooled toroom temperature and 1N NaOH (10 mL) was added. The reaction was thenstirred for 45 minutes at room temperature. The reaction mixture wasextracted with ethyl acetate (3×25 mL) and the organic layer washed with1N NaOH (2×25 mL), H₂O (until pH neutral), brine (50 mL), dried overMgSO₄, concentrated, and subjected to chromatography (on C-18,acetonitrile/H₂O with 0.1% trifluoracetic acid) to afford a white solid(0.19 g, 43%). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (br s, 1H), 7.67 (d,J=7.65 Hz, 1H), 7.49 (app tt, J=6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H),7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+HC₁₉H₁₂BrF₃N₂O₂ requires 437.0107).

Ex. 312

3-bromo-1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1: Preparation of1-(4-bromo-2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

4-Hydroxy-6-methyl-2-pyrone (30.0 g, 238 mmol) and4-bromo-2,6-difluoroaniline (49.5 g, 238 mmol) were suspended in 50 mlof 1,2-dichlorobenzene in a 250 ml, 3-necked, round bottom flaskequipped with a J-Kem temperature controller probe, a Dean-Stark trap,and a heating mantle. The reaction was heated to 165° C. for 15 minutes,during which, water and some 1,2-dichlorobenzene was collected in theDean-Stark trap. The reaction was allowed to cool to about 80° C. Theflask was placed in an ice bath and about 25 ml of toluene was added andstirred. After about 10 minutes, a precipitate formed. The precipitatewas filtered and washed 3 times with toluene, 3 times with hot water toremove excess pyrone, and dried in vacuo to give a tan solid (22.1 g,29%) ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (br s, 1H), 7.71 (d, J=6.98 Hz,2H), 5.97 (t, J=0.88 Hz, 1H), 5.55 (d, J=2.28 Hz, 1H), 1.91 (s, 3H).LC/MS, t_(r)=1.96 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min with detection 254 nm, at 50° C.) ES-MS m/z 316 (M+H). ES-HRMSm/z 315.9779 (M+H calcd for C₁₂H₈BrF₂NO₂ requires 315.9779).

Step 2: Preparation of1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

1-(4-bromo-2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (fromStep 1) (5.0 g, 15.8 mmol) was stirred briskly at room temperature with2,4-difluorobenzyl bromide (2.23 ml, 17.4 mmol) and K₂CO₃ (3.27 g, 23.7mmol) in 50 ml of dimethylformamide. After stirring overnight, thereaction was poured quickly into 900 ml of cold water. The resultingprecipitate was filtered and washed with water and hexane. The productwas purified using a Biotage silica chromatography system using 20%ethyl acetate/hexanes to give a beige solid (4.32 g, 62%). ¹H NMR (400MHz, CDCl₃) δ 7.41 (app q, J=6.31 Hz, 1H), 7.25 (dd, J=8.33, 1.74 Hz,2H), 6.91 (dt, J=9.2, 0.8 Hz, 1H), 6.86 (dt, J=9.2, 0.8 Hz, 1H), 5.95(d, J=2.56 Hz, 1H), 5.92 (dd, J=2.56, 0.94 Hz, 1H), 5.01 (s, 2H), 1.98(s, 3H). LC/MS, t_(r)=3.04 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 442(M+H). ES-HRMS m/z 442.0057 (M+H calcd for C₁₉H₁₂BrF₄NO₂ requires442.0060).

Step 3: Preparation of the title compound.1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(from Step 2) (500 mg, 1.13 mmol) was stirred at room temperature withN-bromosuccinimide (221 mg, 1.24 mmol) in 5 ml of CH₂Cl₂ for 1.5 hours.The reaction was evaporated on a rotary evaporator and the resultingsolid was washed 4 times with acetonitrile and dried in vacuo to yield awhite solid (478 mg, 92%). ¹H NMR (300 MHz, CDCl₃) δ 7.62 (app q, J=6.64Hz, 1H), 7.31 (d, J=6.85 Hz, 2H), 7.01 (app t, J=8.36 Hz, 1H), 6.96 (dt,J=9.46, 2.21 Hz, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 2.10 (s, 3H); LC/MS,t_(r)=3.17 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 520 (M+H). ES-HRMSm/z 521.9134 (M+H calcd for C₁₉H₁₁Br₂F₄NO₂ requires 521.9146).

Ex. 313

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one

The title compound was produced essentially as in Example 313, using2,4,6-trifluoroaniline instead of 4-bromo-2,6-difluoroaniline. ¹H NMR(300 MHz, CDCl₃) δ 7.62 (app q, J=7.79 Hz, 1H), 7.01 (app dt, J=8.26,2.01 Hz, 1H), 6.95-6.85 (m, 3H), 6.19 (s, 1H), 5.30 (s, 2H), 2.11 (s,3H); LC/MS, t_(r)=2.81 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 460 (M+H). ES-HRMSm/z 459.9954 (M+H calcd for C₁₉H₁₁BrF₅NO₂ requires 459.9966).

Ex. 314

3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one

4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(350 mg, 0.92 mmol) was refluxed with N-chlorosuccinimide (147 mg, 1.1mmol) and dichloroacetic acid (0.038 ml, 0.46 mmol) in 5 ml of CH₂Cl₂overnight. The reaction was evaporated on a rotary evaporator and theresulting solid was washed 4 times with acetonitrile and dried in vacuoto yield a white solid (217 mg, 57%). ¹H NMR (300 MHz, CDCl₃) δ 7.60(app q, J=7.75 Hz, 1H), 7.00 (app dt, J=8.23, 2.05 Hz, 1H), 6.93-6.86(m, 3H), 6.22 (s, 1H), 5.30 (s, 2H), 2.12 (s, 3H); LC/MS, t_(r)=2.78minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 416 (M+H). ES-HRMS m/z 416.0472 (M+H calcd forC₁₉H₁₁ClF₅NO₂ requires 416.0471).

Ex. 315

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one

4-[(2,4-Difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(9.0 g, 23.6 mmol) was heated to 135° C. overnight with SeO₂ (13.1 g,118 mmol) in 75 ml of 1,4-dioxane in a 350 ml sealed glass pressurevessel. The reaction mixture was cooled and placed on a plug of silicagel and washed with 5% methanol in CH₂Cl₂. The filtrate was evaporatedand the resulting solid was washed with diethyl ether and dissolved inhot ethyl acetate. The insoluble Se salts were filtered off and theorganic layer was evaporated. 7.01 g (17.6 mmol) of a 3:1 ratio ofaldehyde to desired alcohol was isolated. The mixture was stirred withNaBH₄ (802 mg, 21.2 mmol) in 30 ml of methanol at room temperature for 1hour. The reaction was evaporated and CH₂Cl₂ and acetonitrile were usedto dissolve the bulk of the solid. The remaining insoluble solid wasfiltered off. The organic layer was washed 3 times with NH₄Cl, driedover MgSO₄ and evaporated. The resulting solid was washed 3 times withdiethyl ether and dried in vacuo to yield a light orange solid (4.35 g,46%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (app q, J=7.92 Hz, 1H), 7.47 (appt, J=8.57 Hz, 2H), 7.35 (dt, J=9.87, 2.42 Hz, 1H), 7.18 (dt, J=8.31,1.71 Hz, 1H), 6.21 (d, J=2.42 Hz, 1H), 6.07 (d, J=2.62 Hz, 1H), 5.67 (brs, 1H), 5.18 (s, 2H), 3.98 (s, 2H); LC/MS, t_(r)=2.31 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 398 (M+H).

Step 2: Preparation of the title compound.4-[(2,4-Difluoroberlzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(from step 1) (2.1 g, 5.28 mmol) was stirred at room temperature withN-bromosuccinimide (1.13 g, 6.34 mmol) in 5 ml CH₂Cl₂ for 2 hours. Thereaction was evaporated on a rotary evaporator and the resulting solidwas washed 4 times with acetonitrile and dried in vacuo to yield a whitesolid (1.35 g, 54%). ¹H NMR (300 MHz, CD₃OD) δ 7.69 (app q, J=6.65 Hz,1H), 7.20 (app t, J=8.36 Hz, 2H), 7.09 (app t, J=8.46 Hz, 2H), 6.88 (s,1H), 5.46 (s, 2H), 4.21 (s, 2H); LC/MS, t_(r)=2.48 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 476 (M+H). ES-HRMS m/z 475.9907 (M+H calcd for C₁₉H₁₁BrF₅NO₃requires 475.9915).

Ex 316

3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one

4-[(2,4-Difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(2.1 g, 5.28 mmol) was refluxed with N-chlorosuccinimide (846 mg, 6.34mmol) and dichloroacetic acid (0.87 ml, 10.56 mmol) in 5 ml CH₂Cl₂overnight. The reaction was evaporated on a rotary evaporator and theresulting oil was triturated with diethyl ether to obtain a solid. Thesolid was washed 4 times with acetonitrile. Chromatography was doneusing a Biotage silica gel system with 60% ethyl acetate/hexanes. Therecovery was poor from the column to give a white solid (109 mg, 5%). ¹HNMR (300 MHz, CD₃OD) δ 7.67 (app q, J=7.85 Hz, 1H), 7.24-7.06 (m, 4H),6.90 (s, 1H), 5.45 (s, 2H), 4.22 (s, 2H); LC/MS, t_(r)=2.71 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 432 (M+H) ES-HRMS m/z 432.0413 (M+H calcd forC₁₉H₁₁ClF₅NO₃ requires 432.0420).

Ex. 317

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one

4-[(2,4-Difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(870 mg, 2.28 mmol) was heated to 100° C. with K₂CO₃ (630 mg, 4.56 mmol)in 5 ml of morpholine for 36 hours. The reaction was added to 200 ml ofcold water and the resulting solid was washed with water and 50:50diethyl ether/hexanes and dried in vacuo to give a beige solid (738 mg,72%). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (app q, J=7.70 Hz, 1H), 6.93-6.85(m, 2H), 6.49 (d, J=10.47 Hz, 2H), 5.96 (d, J=2.41 Hz, 1H), 5.89 (d,J=1.75 Hz, 1H), 5.00 (s, 2H), 3.83 (t, J=4.83 Hz, 4H), 3.19 (t, J=4.84Hz, 4H), 1.99 (s, 3H); LC/MS, t_(r)=3.09 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 449 (M+H). ES-HR/MS m/z 449.1485 (M+H calcd for C₂₃H₂₀F₄N₂O₃requires 449.1483).

Step 2: Preparation of the title compound.0.4-[(2,4-Difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one(from step 1) (500 mg, 1.12 mmol) was stirred at room temperature withN-bromosuccinimide (236 mg, 1.33 mmol) in 5 ml of CH₂Cl₂ for 2 hours.The reaction was evaporated on a rotary evaporator and the resulting oilwas triturated with diethyl ether to obtain a solid. The solid waswashed 4 times with acetonitrile and dried in vacuo to yield a whitesolid (171 mg, 29%). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (app q, J=7.74 Hz,1H), 6.96 (app t, J=8.39 Hz, 1H), 6.86 (dt, J=9.46, 2.28 Hz, 1H), 6.50(d, J=10.74 Hz, 2H), 6.09 (s, 1H), 5.24 (s, 2H), 3.84 (t, J=4.84 Hz,4H), 3.20 (t, J=4.83 Hz, 4H), 2.07 (s, 3H); LC/MS, t_(r)=3.18 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 527 (M+H). ES-HRMS m/z 527.0570 (M+H calcd forC₂₃H₁₉BrF₄N₂O₃ requires 527.0588).

Ex. 318

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one

The title compound was prepared essentially as in Example 317, using1-methylpiperazine instead of morpholine. ¹H NMR (400 MHz, CDCl₃) δ 7.57(app q, J=7.79 Hz, 1H), 6.96 (dt, J=8.19, 1.88 Hz, 1H), 6.86 (app dt,J=9.44, 2.48 Hz, 1H), 6.52 (d, J=10.61 Hz, 2H), 6.14 (s, 1H), 5.24 (s,2H), 3.72 (br s, 4H), 3.51 (d, J=11.27 Hz, 2H), 3.07 (br s, 2H), 2.85(d, J=4.29 Hz, 3H), 2.06 (s, 3H); LC/MS, t_(r)=2.50 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 540 (M+H). ES-HRMS m/z 540.0930 (M+H calcd for C₂₄H₂₂BrF₄N₃O₂requires 540.0904).

Ex. 320

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one

4-[(2,4-Difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl]-6-methylpyridin-2(1H)-one(1.3 g, 2.82 mmol) was stirred at reflux with N-chlorosuccinimide (451mg, 3.38 mmol) and dichloroacetic acid (0.17 ml, 1.41 mmol) in 6 mlCH₂Cl₂ overnight. LC-MS showed 33% completion. More N-chlorosuccinimide271 mg, 2.23 mmol) was added and refluxed overnight. The reaction wasevaporated on a rotary evaporator and the resulting oil was trituratedwith ethyl acetate to obtain a solid. The solid was washed 4 times withethyl acetate and with diethyl ether and dried in vacuo to obtain awhite solid (606 mg, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (br q,J=7.74 Hz, 1H), 7.33 (br t, J=9.00 Hz, 1H), 7.16 (br t, J=7.65 Hz, 1H),6.96 (d, J=11.81 Hz, 2H), 6.79 (s, 1H), 5.33 (s, 2H), 3.61 (br m, 4H),3.25 (br m, 4H), 3.21 (br s, 3H), 2.04 (s, 3H); LC/MS, t_(r)=2.45minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 496 (M+H). ES-HRMS m/z 496.1400 (M+H calcd forC₂₄H₂₂ClF₄N₃O₂ requires 496.1409).

Example 321

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(dimethylamino)2,6-difluorophenyl]-6-methylpyridin-2(1H)-one

The title compound was prepared essentially as described in Example 317,using dimethylamine instead of morpholine. ¹H NMR (400 MHz, CDCl₃) δ7.59 (q, J=7.74 Hz, 1H), 6.95 (dt, J=8.32, 1.61 Hz, 1H), 6.85 (app dt,J=9.54, 2.41 Hz, 1H), 6.27 (d, J=11.01 Hz, 2H), 6.08 (s, 1H), 5.23 (s,2H), 2.98 (s, 3H), 2.07 (s, 3H); LC/MS, t_(r)=3.35 minutes (5 to 956acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0447 (M+H calcd for C₂₁H₁₇BrF₄N₂O₂requires 485.0482).

Example 322

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one

The title compound was prepared essentially as in Example 317, using2-(methylamino)ethanol instead of morpholine.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (q, J=7.74 Hz, 1H), 6.95 (dt, J=8.24,1.66 Hz, 1H), 6.85 (app dt, J=9.49, 2.37 Hz, 1H), 6.35 (d, J=11.01 Hz,2H), 6.10 (s, 1H), 5.23 (s, 2H), 3.77 (t, J=5.77 Hz, 2H), 3.45 (t,J=5.78 Hz, 2H), 2.99 (s, 3H), 2.08 (s, 3H); LC/MS, t_(r)=2.96 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0576 (M+H calcd forC₂₂H₁₉BrF₄N₂O₃ requires 515.0588).

Example 323

3-bromo-1-(3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(1H)-one

4-[(2,4-Difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(step 2 above) (10.0 g, 26.2 mmol) was heated to 45° C. with KOSiMe₃(10.08 g, 78.6 mmol) in 50 ml of tetrahydrofuran for 4 days. Thereaction was diluted with 30 ml of ethyl acetate and washed with 1N HCland water, dried over MgSO₄, and evaporated to give an orange solid. Thesolid was stirred in hot 60% ethyl acetate/hexanes and filtered to givea white solid, which was dried in vacuo to obtain a white solid (3.79 g,38%). The filtrate was found to contain a mixture of desired product andthe ortho substituted regioisomer. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (appq, J=7.70 Hz, 1H), 6.95-6.83 (m, 2H), 6.34 (d, J=9.40 Hz, 2H), 6.05 (apps, 2H), 5.06 (s, 2H), 2.01 (s, 3H); LC/MS, t_(r)=2.80 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 380 (M+H). ES-HRMS m/z 380.0926 (M+H calcd for C₁₉H₁₃F₄NO₃requires 380.0904).

Step 2: Preparation of the title compound.4-[(2,4-Difluorobenzyl)oxy]-1-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(1H)-one(from step 1) (3.73 g, 8.14 mmol) was stirred as a suspension at roomtemperature with N-bromosuccinimide (1.52 g, 8.55 mmol) in 30 ml CH₂Cl₂overnight. LC-MS showed a 60% starting material. The solid was filteredoff, dissolved in 30 ml of CH₂Cl₂/N,N-dimethylformamide and stirred withmore N-bromosuccinimide (0.76 g, 4.28 mmol) overnight. LC-MS showed thetri-brominated product as the major product. The reaction was pouredinto water and extracted with n-butanol. The combined organic layerswere evaporated on a rotary evaporator and the resulting solid waswashed with diethyl ether and dried in vacuo to yield a white solid (873mg, 17%). ¹H NMR (400 MHz, CDCl₃) δ 7.67 (app q, J=7.80 Hz, 1H), 7.32(dt, J=4.86, 2.11 Hz, 1H), 7.16 (dt, J=8.48, 1.84 Hz, 1H), 6.79 (s, 1H),5.35 (s, 2H), 2.08 (s, 3H); LC/MS, t_(r)=3.26 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 616 (M+H). ES-HRMS m/z 615.8234 (M+H calcd for C₁₉H₁₀Br₃F₄NO₃requires 615.8200).

Example 324

2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}acetamideStep 1: Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(1H)-one

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2,4,6-trifluorophenyl)pyridin-2(1H)-one(above) (7.5 g, 16.3 mmol) was heated to 45° C. with KOSiMe₃ (10.08 g,78.6 mmol) in 50 ml of tetrahydrofuran for 48 hours. The reaction wasdiluted with 30 ml of ethyl acetate and washed with 1N HCl and water,dried over MgSO₄, and evaporated to give a black oil. The oil wasdissolved in ethyl acetate. A precipitate formed upon standing, whichwas filtered, washed with ethyl acetate and dried in vacuo to obtain awhite solid (2.80 g, 37%). The filtrate showed the presence of desiredproduct and the ortho substituted regioisomer. ¹H NMR (400 MHz, DMSO-d₆)δ 7.66 (q, J=7.92 Hz, 1H), 7.32 (dt, J=8.77, 2.19 Hz, 1H), 7.15 (m, 1H),6.73 (s, 1H), 6.67 (d, J=9.66 Hz, 2H), 5.33 (s, 2H), 2.03 (s, 3H);LC/MS, t_(r)=2.92 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 458 (M+H). ES-HRMS m/z457.9995 (M+H calcd for C₁₉H₁₂BrF₄NO₃ requires 458.0009).

Step 2: Preparation of the title compound.3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(1H)-one(from step 1) (500 mg, 1.09 mmol) was stirred briskly with2-bromoacetamide (196 mg, 1.43 mmol) and K₂CO₃ (282 mg, 2.05 mmol) in 5ml of N,N-dimethylformamide at room temperature for 24 hours. Thereaction was poured quickly into cold water and the resulting solid wasfiltered, washed with water, acetonitrile, and diethyl ether, and driedin vacuo to give a white solid (289 mg, 51%). ¹H NMR (400 MHz, DMSO-d₆)δ 7.66 (q, J=7.92 Hz, 1H), 7.61 (br s, 1H), 7.45 (br s, 1H), 7.33 (dt,J=10.07, 2.15 Hz, 1H), 7.16 (dt, J=8.53, 1.88 Hz, 1H), 6.99 (d, J=9.54Hz, 2H), 6.76 (s, 1H), 5.34 (s, 2H), 2.03 (s, 3H); LC/MS, t_(r)=2.70minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0245 (M+H calcd forC₂₁H₁BrF₄N₂O₄ requires 515.0224).

Example 325

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(2-hydroxyethoxy)phenyl]-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for Example 324. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (q, J=7.92Hz, 1H), 7.33 (dt, J=10.04, 2.19 Hz, 1H), 7.17 (dt, J=8.68, 1.84 Hz,1H), 6.99 (d, J=9.67 Hz, 2H), 6.75 (s, 1H), 5.34 (s, 2H), 4.92 (t,J=4.86 Hz, 1H), 4.07 (t, J=4.77 Hz, 2H), 3.70 (t, J=4.83 Hz, 2H), 2.03(s, 3H); LC/MS, t_(r)=2.81 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 502 (M+H). ES-HRMSm/z 502.0291 (M+H calcd for C₂₁H₁₆BrF₄NO₄ requires 502.0272).

Example 326

3-bromo-1-(2,6-difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-oneStep 1: Preparation of1-(2,6-difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one

1-(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (step 1) (3.0g, 12.65 mmol) was dissolved in N,N-dimethylformamide and cooled to 0°C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate(2.39 ml, 15.18 mmol) were added and stirred for 10 minutes.1,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was addedand stirred at 0° C. for 1 hour, then allowed to warm to roomtemperature and stirred overnight. LC-MS showed only 1 product, not amixture of regioisomers, as expected. The reaction was added to waterand extracted 3 times with ethyl acetate. The combined organic layerswere dried over MgSO₄ and evaporated. A Biotage silica column was doneusing 60% ethyl acetate/hexanes as an eluent. Desired product, with asubstantial impurity was obtained. Another Biotage silica column was ranusing 30% ethyl acetate/hexanes to obtain pure product. The resultingoil was triturated with diethyl ether to obtain a white solid (720 mg,15%). ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.39 (m, 2H), 7.26 (dd, J=9.62,2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J=2.42 Hz, 1H), 5.96 (d,J=2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s,3H); LC/MS, t_(r)=2.37 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 376 (M+H).ES-HR/MS m/z 376.1181 (M+H calcd for C₂₀H₁₆F₃NO₃ requires 376.1155).Identity of the positional isomer was determined from hmbc, 2-D NMRexperiments using H to C₂- and 3-bond coupling.

Step 2: Preparation of the title compound.1-(2,6-Difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one(from step 1) (350 mg, 0.93 mmol) was stirred at room temperature withN-bromosuccinimide (199 mg, 1.12 mmol) in 1.5 ml CH₂Cl₂ for 1.5 hours.The reaction was evaporated on a rotary evaporator and the resultingsolid was washed 4 times with acetonitrile and dried in vacuo to yield awhite solid (197 mg, 47%). ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.43 (m, 2H),7.25 (dd, J=9.46, 2.62 Hz, 1H), 7.11-7.03 (m, 3H), 6.25 (s, 1H), 5.31(s, 2H), 4.81 (s, 2H), 2.28 (br s, 1H), 2.10 (s, 3H); LC/MS, t_(r)=2.38minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0247 (M+H calcd forC₂₀H₁₅BrF₃NO₃ requires 454.0260).

Example 327

3-chloro-1-(2,6-difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one

1-(2,6-Difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(1H)-one(step 1 above) (275 mg, 0.73 mmol) was stirred at reflux withN-chlorosuccinimide (117 mg, 0.88 mmol) and dichloroacetic acid (0.03ml, 0.36 mmol) in 1.5 ml CH₂Cl₂ overnight. The reaction was evaporatedon a rotary evaporator and the resulting solid was washed 4 times withethyl acetate and with diethyl ether and dried in vacuo to obtain awhite solid (65.5 mg, 22%). ¹H NMR (300 MHz, CDCl₃) δ 7.52-7.43 (m, 2H),7.26 (dd, J=9.38, 2.52 Hz, 1H), 7.12-7.04 (m, 3H), 6.27 (s, 1H), 5.32(s, 2H), 4.82 (s, 2H), 2.29 (br s, 1H), 2.11 (s, 3H); LC/MS, t_(r)=2.32minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 410 (M+H). ES-HRMS m/z 410.0755 (M+H calcd forC₂₀H₁₅ClF₃NO₃ requires 410.0765).

Example 328

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin1(2H)-yl]-2-methyl-N-(2-morpholin-4-ylethyl)benzamide Step 1:Preparation of methyl3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-methylbenzoate

4-Hydroxy-6-methyl-2-pyrone (72.6 g, 576 mmol) andmethyl-3-amino-2-methylbenzoate (100 g, 605 mmol) were suspended in 75ml of 1,2-dichlorobenzene in a 500 ml, 3-necked round bottom flaskequipped with a J-Kem temperature controller probe, a Dean-Stark trap,and a heating mantle. The reaction was heated to 165° C. for 15 minutes,during which, water and some 1,2-dichlorobenzene was collected in theDean-Stark trap. The reaction was allowed to cool to about 80° C. Theflask was placed in an ice bath and about 300 ml of toluene was addedand stirred. After about 30 minutes, a precipitate formed. Theprecipitate was filtered and washed 3 times with toluene, 3 times withhot water to remove excess pyrone, and dried in vacuo to give a tansolid (44.6 g, 28% yield). ¹H NMR (400 MHz, DMSO d₆) δ 10.66 (br s, 1H),7.80 (dd, J=7.72, 1.28 Hz, 1H), 7.33 (dd, J=7.78, 1.34 Hz, 1H), 5.91(dd, J=2.41, 0.69 Hz, 1H), 5.55 (d, J=2.42 Hz, 1H), 3.82 (s, 3H), 2.06(s, 3H), 1.73 (s, 3H); LC/MS, t_(r)=1.85 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1078 (M+H calcd for C₁₅H₁₅NO₄requires 274.1074).

Step 2: Preparation of methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoate

Methyl-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-methylbenzoate(from Step 1) (42.0 g, 154 mmol) was stirred briskly at room temperaturewith 2,4-difluorobenzyl bromide (19.7 ml, 154 mmol) and K₂CO₃ (31.8 g,231 mmol) in 250 ml of N,N-dimethylformamide. After stirring overnight,the reaction was poured into 1 L of cold water. The solution wasextracted 3 times with ethyl acetate and the organic layers were driedover MgSO₄, and evaporated. The product was carried on to the next stepas a crude oil (60.4 g, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd,J=7.85, 1.28 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-7.23 (m, 1H), 6.94-6.84(m, 2H), 5.98 (d, J=2.68 Hz, 1H), 5.92 (dd, J=2.69, 0.81 Hz, 1H), 5.01(s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H); LC/MS, t_(r)=2.96minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1341 (M+H calcd forC₂₂H₁₉F₂NO₄ requires 400.1355).

Step 3: Preparation of3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid

Methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoate(from Step 2) (60.0 mg, 150 mmol) was stirred with 2.5 N NaOH (120 ml,300 mmol) in 375 ml of tetrahydrofuran and 75 ml of water at roomtemperature overnight. The reaction was acidified with 1 N HCl, 350 mlof water was added and the solution was extracted 3 times with ethylacetate. The combined organic layers were dried over MgSO₄, filtered andevaporated. The resulting solid was filtered, washed with ethyl acetateand dried in vacuo to yield a white solid 33.8 g, 58%). ¹H NMR (400 MHz,CDCl₃) δ 7.98 (dd, J=7.92, 1.20 Hz, 1H), 7.43 (app q, J=7.70 Hz, 1H),7.38 (t, J=7.72 Hz, 1H), 7.35 (dd, J=7.81, 1.21 Hz, 1H), 6.92-6.84 (m,2H), 6.17 (d, J=2.56 Hz, 1H), 6.00 (dd, J=2.55, 0.81 Hz, 1H), 5.05 (s,2H), 2.30 (s, 3H), 1.84 (s, 3H); LC/MS, t_(r)=2.61 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 386 (M+H). ES-HR/MS m/z 386.1228 (M−H calcd for C₂₁H₁₇F₂NO₄requires 386.1198).

Step 4: Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid

3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (from Step 3) (23.0 g, 59.7 mmol) was stirred at room temperaturewith N-bromosuccinimide (12.74 g, 71.6 mmol) in 120 ml of CH₂Cl₂ for 2hours. The reaction was evaporated on a rotary evaporator and theresulting solid was stirred in acetonitrile for 1 hour, washed 7 timeswith acetonitrile and dried in vacuo to yield a white solid (19.14 g,69%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (dd, J=7.52, 1.61 Hz, 1H), 7.67(app q, J=7.92 Hz, 1H), 7.45 7.37 (m, 2H), 7.33 (dt, J=9.87, 2.54 Hz,1H), 7.17 (dt, J=8.50, 1.67 Hz, 1H), 6.71 (s, 1H), 5.32 (s, 2H), 2.08(s, 3H), 1.86 (s, 3H); LC/MS, t_(r)=2.69 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0284 (M+H calcd for C₂₁H₁₆BrF₂NO₄requires 464.0304).

Step 5: Preparation of the title compound3-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (from Step 4 above) (500 mg, 1.08 mmol) was dissolved in 5 ml ofCH₂Cl₂. 4-(2-Aminoethyl)morpholine (170 μl, 1.29 mmol) was added,followed, in order, by EDCI (247 mg, 1.29 mmol), 1-hydroxybenzotriazole(174 mg, 1.29 mmol) and triethylamine (301 μl, 2.16 mmol). The reactionwas stirred at room temperature overnight. The reaction was quenchedwith NH₄Cl and extracted 3 times with ethyl acetate. The combinedorganic layer was dried over MgSO₄ and evaporated. The resulting oil wastriturated with diethyl ether/hexane to obtain a solid, which was driedin vacuo to give a white solid (472 mg, 76%). ¹H NMR (400 MHz, DMSO-d₆)δ 7.64 (app q, J=7.79 Hz, 1H), 7.47 (dd, J=7.65, 1.01 Hz, 1H), 7.39 (t,J=7.75 Hz, 1H), 7.17 (dd, J=7.65, 0.81 Hz, 1H), 7.01 (dt, J=8.26, 1.61Hz, 1H), 6.91 (dt, J=9.42, 2.32 Hz, 1H), 6.49 (t, J=5.04 Hz, 1H), 6.18(s, 1H), 5.30 (s, 2H), 3.73 (t, J=4.53 Hz, 4H), 3.68-3.47 (m, 21), 2.59(t, J=5.94 Hz, 2H), 2.51 (t, J=4.33 Hz, 4H), 2.15 (s, 3H), 1.98 (s, 3H);LC/MS, t_(r)=2.27 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 576 (M+H) ES-HRMS m/z576.1313 (M+H calcd for C₂₇H₂₈BrF₂N₂O₄ requires 576.1304).

Examples 329-337

The following compounds are prepared essentially according to theprocedure set forth for Example 328:

Example M + H ESHRMS No. R MF Requires m/z Ex. 329 —NHCH₂CH₂OCH₃C₂₄H₂₂BrF₂N₂O₄ 521.0882 521.0906 Ex. 330 —N(CH₃)₂ C₂₃H₂₀BrF₂N₂O₃491.0776 491.0752 Ex. 331 —NHCH₂CH₂OH C₂₃H₂₀BrF₂N₂O₄ 507.0726 507.0689Ex. 332 —NHCH₃ C₂₂H₁₈BrF₂N₂O₃ 477.0620 477.0585 Ex. 333 —N(CH₃)CH₂CH₂OHC₂₄H₂₂BrF₂N₂O₄ 521.0882 521.0890 Ex. 334 4-methylpiperazin-1-ylC₂₆H₂₅BrF₂N₃O₃ 546.1198 546.1187 Ex. 335 morpholin-4-yl C₂₅H₂₂BrF₂N₂O₄533.0882 533.0856 Ex. 336 —N(CH₃)CH₂CH₂OCH₃ C₂₅H₂₄BrF₂N₂O₄ 535.1039535.1055 Ex. 337 —NH₂ C₂₁H₁₆BrF₂N₂O₃ 463.0463 463.0492

NMR characterization of compounds of Examples 329-337 Example No. NMRData Ex.329 ¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q, J = 7.79 Hz, 1H),7.47 (dd, J = 7.65, 1.08 Hz, 1H), 7.34 (t, J = 7.72 Hz, 1H), 7.12 (dd, J= 7.78, 0.94 Hz, 1H), 6.96 (app dt, J = 7.92, 2.27 Hz, 1H), 6.87 (dt, J= 9.46, 2.55 Hz, 1H), 6.29 (m, 1H), 6.12 (s, 1H), 5.25 (s, 2H), 3.73 −3.65 (m, 1H), 3.56 − 3.48 (m, 3H), 3.35 (d, J = 3.09 Hz, 3H), 2.09 (s,3H), 1.93 (s, 3H) Ex. 330 ¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q, J =7.79 Hz, 1H) 7.34 (t, J = 7.66 Hz, 1H), 7.28 (dd, J = 7.66, 1.21 Hz,1H), 7.07 (dd, J = 7.65, 1.08 Hz, 1H), 6.96 (app dt. J = 8.52, 2.02 Hz,1H), 6.87 (dt, J = 9.46, 2.55 Hz, 1H), 6.29 (m, 1H), 6.12 (s, 1H), 5.25(s, 2H), 3.11 (s, 3H), 2.82 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H) Ex.331¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q, J = 7.74 Hz, 1H), 7.46 (d, J =6.71 Hz, 1H), 7.32 (t, J = 7.72 Hz, 1H), 7.07 (d, J = 6.85 Hz, 1H), 6.98(m, 2H), 6.87 (dt, J = 9.47, 2.41 Hz, 1H), 6.15 (s, 1H), 5.26 (s, 2H),3.71 (t, J = 4.97 Hz, 2H), 3.60 −3.45 (m, 2H), 2.06 (s, 3H), 1.95 (s,3H) Ex. 332 ¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q, J = 7.79 Hz, 1H),7.42 (dd, J = 7.66, 0.94 Hz, 1H), 7.31 (t, J = 7.72 Hz, 1H), 7.09 (dd, J= 7.79, 0.94 Hz, 1H), 6.96 (app dt, J = 8.26, 1.61 Hz, 1H), 6.87 (dt, J= 9.44, 2.49 Hz, 1H), 6.12 (s, 1H), 5.25 (s, 2H), 2.96 (d, J = 4.83 Hz,3H), 2.07 (s, 3H), 1.93 (s, 3H) Ex. 333 ¹H NMR (300 MHz, DMSO-d₆) δ 7.73(q, J = 7.92 Hz, 1H), 7.44 − 7.20 (m, 5H), 6.75 (s, 1H), 5.37 (s, 2H),4.83 (br s, 1H), 3.65 (br s, 2H), 3.45 − 3.33 (m, 2H), 2.81 (s, 3H),1.93 (d, J = 3.42 Hz, 3H), 1.85 (d, J = 8.06 Hz, 3H) Ex. 334 ¹H NMR (300MHz, DMSO-d₆) δ 7.67 (app q, J = 7.92 Hz, 1H), 7.40 (t, J = 7.78 Hz,1H), 7.34 (dt, J = 9.87, 2.55 Hz, 1H), 7.27 (d, J = 7.52 Hz, 1H), 7.24(d, J = 7.79 Hz, 1H) , 7.17 (dt, J = 8.41, 1.97 Hz, 1H), 6.71 (s, 1H),5.32 (s, 2H), 3.63 (m, 2H), 3.29 (br s, 1H), 3.09 (br s, 2H), 2.34 (t, J= 4.57 Hz, 2H), 2.20 (br s, 2H), 2.16 (s, 3H), 1.88 (d, J = 8.86 Hz,3H), 1.80 (d, J = 4.83 Hz, 3H) Ex. 335 ¹H NMR (300 MHz, CDCl₃) δ 7.64(app q, J = 7.79 Hz, 1H), 7.42 (t, J = 7.65 Hz, 1H), 7.33 (d, J = 7.66Hz, 1H), 7.14 (d, J = 7.65 Hz, 1H), 7.00 (dt, J = 8.76, 2.21 Hz, 1H),6.91 (dt, J = 9.47, 2.42 Hz, 1H), 6.17 (s, 1H), 5.29 (s, 2H), 3.98 −3.92 (m, 1H), 3.80 − 3.77 (m, 3H), 3.59 (br s, 2H), 3.29 (t, J = 4.43Hz, 2H), 2.04 (s, 3H), 2.00 (s, 3H) Ex. 336 ¹H NMR (300 MHz, CDCl₃) δ7.65 (app q, J = 7.79 Hz, 1H), 7.43 − 7.32 (m, 2H), 7.12 (dd, J = 7.66,1.21 Hz, 1H), 7.00 (dt, J = 9.06, 1.51 Hz, 1H), 6.92 (dt, J = 9.42, 2.52Hz, 1H), 6.16 (s, 1H), 5.30 (s, 2H), 3.69 (t, J = 5.04 Hz, 2H), 3.39 (s,3H), 3.26 (s, 1H), 3.19 (s, 1H), 2.91 (s, 3H), 2.04 (s, 3H), 2.00 (s,3H) Ex. 337 ¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (br s, 1H), 7.73 (app q, J= 7.85 Hz, 1H), 7.53 − 7.20 (m, 5H), 6.74 (s, 1H), 5.37 (s, 2H), 1.99(s, 3H), 1.92 (s, 3H)

Example 338

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

3-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (Step 4 above) (2.0 g, 4.31 mmol) was cooled to 0° C. in 10 ml oftetrahydrofuran. 19.5 ml of 1M BH₃-THF in tetrahydrofuran was added andstirred overnight, allowing the temperature to rise to room temperature.The reaction was cooled back down to 0° C. and ice chips were added toquench the reaction. The slurry was extracted 3 times with an ethylacetate/tetrahydrofuran mixture. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and evaporated to give a whitesolid (1.73 g, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (app q, J=7.92 Hz,1H), 7.46 (d, J=7.52 Hz, 1H), 7.32 (dt, J=10.74, 2.42 Hz, 1H), 7.30 (t,J=7.72 Hz, 1H), 7.17 (dt, J=8.46, 1.88 Hz, 1H), 7.03 (d, J=7.38 Hz, 1H),6.68 (s, 1H), 5.32 (s, 2H), 4.51 (s, 2H), 3.29 (d, J=9.40 Hz, 1H), 1.85(s, 3H), 1.81 (s, 3H), LC/MS, t_(r)=2.64 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 450 (M+H). ES-HRMS m/z 450.00480 (M+H calcd for C₂₁H₁₈BrF₂NO₃requires 450.0511).

Example 339

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-methoxyethyl)-2-methylbenzamideStep 1: Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid

3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (Step 3 above) (10.0 g, 25.9 mmol) was refluxed withN-chlorosuccinimide (4.15 g, 31.1 mmol) and dichloroacetic acid (1.06ml, 12.9 mmol) in 50 ml of CH₂Cl₂ overnight. The reaction was evaporatedon a rotary evaporator and the resulting solid was stirred inacetonitrile for 30 minutes, washed 4 times with acetonitrile and driedin vacuo to yield a white solid (8.3 g, 78%). ¹H NMR (300 MHz, DMSO-d₆)δ 7.93 (dd, J=7.15, 1.92 Hz, 1H), 7.72 (app q, J=7.92 Hz, 1H), 7.52-7.35(m, 3H), 7.22 (dt, J=8.47, 2.01 Hz, 1H), 6.80 (s, 1H), 5.38 (s, 2H),2.14 (s, 3H), 1.93 (s, 3H); LC/MS, t_(r)=2.64 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0806 (M+H calcd for C₂₁H₁₆ClF₂NO₄requires 420.0809).

Step 5: Preparation of the title compound.3-[3-Chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (from Step 1 above) (500 mg, 1.19 mmol) was dissolved in 5 ml ofCH₂Cl₂. 2-Methoxyethylamine (129 μl, 1.49 mmol) was added, followed, inorder, by EDCI (286 mg, 1.49 mmol), 1-hydroxybenzotriazole (202 mg, 1.49mmol) and triethylamine (332 μl, 2.38 mmol). The reaction was stirred atroom temperature overnight. The reaction was quenched with NH₄Cl andextracted 3 times with ethyl acetate. The combined organic layer wasdried over MgSO₄ and evaporated. The resulting solid was dried in vacuoto give a white solid (401 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.56 (appq, J=7.74 Hz, 1H), 7.47 (d, J=6.98 Hz, 1H), 7.34 (t, J=7.72 Hz, 1H),7.11 (d, J=7.25 Hz, 1H), 6.95 (dt, J=8.23, 1.66 Hz, 1H), 6.87 (dt,J=9.51, 2.46 Hz, 1H), 6.35 (br s, 1H), 6.15 (s, 1H), 5.25 (s, 2H),3.72-3.63 (m, 1H), 3.58-3.49 (m, 3H), 3.35 (s, 3H), 2.09 (s, 3H), 1.93(s, 3H); LC/MS, t_(r)=2.56 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 477 (M+H). ES-HRMSm/z 477.1363 (M+H calcd for C₂₄H₂₃ClF₂N₂O₄ requires 477.1387).

Example 340

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,2-dimethylbenzamide

The title compound was prepared by a procedure similar to the onedescribed for Example 337, where methylamine was used as the amine andthe product was obtained in 73% yield. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37(app d, J=4.64 Hz, 1H), 7.72 (app q, J=7.92 Hz, 1H), 7.44-7.35 (m, 4H),7.22 (dt, J=8.54, 1.61 Hz, 1H), 6.78 (s, 1H), 5.37 (s, 2H), 2.79 (d,J=4.43 Hz, 3H), 1.95 (s, 3H), 1.94 (s, 3H); LC/MS, t_(r)=2.46 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1163 (M+H calcd forC₂₂H₁₉ClF₂N₂O₃ requires 433.1125).

Example 341

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-2-methylbenzamide

The title compound was prepared by a procedure similar to the onedescribed for, where ethanolamine was used as the amine and the productwas obtained in 65% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (t, J=5.51Hz, 1H), 7.67 (app q, J=7.88 Hz, 1H), 7.43-7.33 (m, 3H), 7.23 (d, J=7.25Hz, 1H), 7.17 (dt, J=8.39, 1.66 Hz, 1H), 6.74 (s, 1H), 5.32 (s, 2H),3.48 (br s, 2H), 3.31-3.26 (m, 2H), 1.90 (s, 3H), 1.89 (s, 3H); LC/MS,t_(r)=2.34 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min, at 254 nm, at 50° C.), ES-MS m/z 463 (M+H). ES-HRMS m/z 463.1220(M+H calcd for C₂₃H₂₁ClF₂N₂O₄ requires 463.1231).

Example 342

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzamide

3-[3-Chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-methylbenzoicacid (Step 1 above) (500 mg, 1.19 mmol) was stirred with2-chloro-4,6-dimethoxy-1,3,5-triazine (251 mg, 1.43 mmol) andN-methylmorpholine (392 μl, 3.57 mmol) in 5 ml of tetrahydrofuran atroom temperature for 2 hours. 2.5 ml of NH₄OH was added and stirred atroom temperature for 2.5 hours. The reaction was diluted withtetrahydrofuran and ethyl acetate and extracted. The combined organiclayers were washed with NaHCO₃, 1 N HCl, and brine, dried over MgSO₄,filtered and evaporated. The resulting solid was dried in vacuo toobtain a white solid (313 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (brs, 1H), 7.66 (q, J=7.83 Hz, 1H), 7.48-7.30 (m, 3H), 7.23 (d, J=7.52 Hz,1H), 7.17 (t, J=7.65 Hz, 1H), 6.73 (s, 1H), 5.32 (s, 2H), 1.94 (s, 3H),1.88 (s, 3H); LC/MS, t_(r)=2.44 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES MS m/z 419 (M+H).ES-HRMS m/z 419.0963 (M+H calcd for C₂₁H₁₇ClF₂N₂O₃ requires 419.0969).

Example 343

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrileStep 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide

2,4-difluorobenzyl alcohol (100. g, 0.694 mol) and 4-nitropyridineN-oxide (98. g, 0.700 mol)are combined with 250 g Cs₂CO₃ (1.1 eq) in 2.5L anhydrous dimethylformamide and heated to 80° C. with stirring. Thereaction was followed by ¹⁹F-NMR (crude reaction mixture with externalD₂O reference) and complete after 40 h. The mixture was filtered hot;product crystallized out on cooling. 90.21 g (55%) of white plates werecollected by filtration and washed with diethyl ether. The mother liquorwas diluted with 2.5 L diethyl ether and stored in the freezerovernight, yielding a second crop 68.76 g (41%, combined yield 96%).¹H-NMR (400 MHz, DMSO-d₆) δ 8.06 (m, 2H), 7.61 (quartet, J=8.45 Hz, 1H),7.30 (t, J=10.37 Hz, 1H), 7.12, (t, J=8.45 Hz, 1H), 7.09 (d, J=5.06 Hz,2H), 5.14 (s, 2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.43 (quintet, J=7.78Hz, 1F), −113.82 (quartet, J=9.55 Hz, 1F). LC/MS t_(r)=3.90 minutes(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 238 (M+H).

Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-pyridin-2(1H)-one (7)

4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide (from Step 1) (30.0 g, 0.127mol), anhydrous potassium acetate (25 g, 0.25 mol), acetic anydride (25g, 0.25 mol), and 10 ml acetic acid were combined in a 250-mlround-bottomed flask with overhead stirring and heated to 130° C. for 4hours. The mixture was concentrated under vacuum, the solids dissolvedin 95 ml acetonitrile; 5 ml water, filtered through charcoal and pouredinto 600 ml ice with stirring. The mixture was allowed to standovernight at room temperature, then 9.62 g (30%) product collected byfiltration as a medium brown solid (adequate for the next step withoutpurification). ¹H-NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.59 (quartet,J=9.91 Hz, 1H), 7.29 (t, J=10.36 Hz, 1H), 7.21 (d, J=8.20 Hz, 1H), 7.11(t, J=8.48 Hz, 1H), 5.83 (m, 2H), 5.02 (s, 2H). ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −109.57 (quintet, J=7.66 Hz, 1F)-113.88 (quartet, J=8.93 Hz,1F). LC/MS t_(r)=4.29 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254nm, at 50° C.) ES-MS m/z 238 (M+H).

Step 3: Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one

4-[(2,4-difluorobenzyl)oxy]-pyridin-2(1H)-one (from Step 2) (8.60 g,36.3 mmol) was stirred in 150 ml dimethylformamide and treated withN-chlorosuccinimide (5.4 g, 39.9 mmol). After 15 hours, the precipitatewas collected by filtration (5.11 g, 52%) yielding a lustrous whitesolid. The mother liquor was diluted to 500 ml with diethyl ether,providing 2.47 g (25%) in a second crop. ¹H-NMR (400 MHz, DMSO-d₆) δ11.87 (s, 1H), 7.60 (quartet, J=6.34 Hz, 1H), 7.43 (d, J=7.58 Hz, 1H),7.31 (dt, J=10.08, 2.21 Hz, 1H), 7.14 (dt, J=8.65, 1.79 Hz, 1H), 6.44(d, J=7.49 Hz, 1H), 5.28 (s, 1H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.58(quintet, J=7.75 Hz, 1F), −113.68 (quartet, J=8.68 Hz, 1F). LC/MSt_(r)=4.47 minutes (0-95% acetonitrile/water, 0.05% trifluoroaceticacid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.)ES-MS m/z 272, 274 3:1 (M+H).

Step 4: Preparation of the Title Compound

3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one (from step 3)(3.25 g, 11.9 mmol) was combined with Cs₂CO₃ (3.93 g, 12.1 mmol) in 50ml dimethylformamide and heated to 70° C., stirring under nitrogen.3,4,5-trifluorobenzonitrile (1.83 g, 11.9 mmol) was added. After 4hours, the mixture was filtered, concentrated in vacuo, washed thricewith hot cyclohexane, dissolved in tetrahydrofuran, treated with MgSO₄and charcoal, and filtered. The solution was evaporated leaving a finewhite solid (3.99 g, 82%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J=7.59Hz, 2H), 7.92 (d, J=8.31 Hz, 1H), 7.65 (quartet, J=6.77, 1H), 7.34 (dt,J=9.81, 2.71 Hz, 1H), 7.16 (dt, J=8.59, 2.50 Hz, 1H), 6.87 (d, J=8.01Hz, 1H), 5.39 (s, 2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.17 (quintet,J=8.97 Hz, 1F), −113.51 (quartet, J=9.53 Hz, 1F), −116.32 (d, J=7.69 Hz,2F). LC/MS t_(r)=5.51 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215nm, at 50° C.) ES MS m/z 409 (M+H). ES-HRMS m/z 409.0351 (M+H calcd forC₁₉H₁₀ClF₄N₂O₂ requires 409.0361).

Example 344

1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride Step 1: Preparation of tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile(2.84 g, 6.95 mmol), di-t-butyl-dicarbonate (3.18 g, 14.6 mmol), andnickel(II) chloride (0.90 g, 6.95 mmol) were combined with 40 mlmethanol and 40 ml tetrahydrofuran and cooled to 0° C. stirring in anice bath. Sodium borohydride (1.33 g, 35.2 mmol) was added in smallportions over 10 minutes to control foaming, and the reaction wasstirred 1 hour. Additional sodium borohydride (0.50 g, 13.2 mmol) wasrequired to force the reaction to completion by LC. A color change fromyellow to black persisted on completion. The mixture was filteredthrough a bed of charcoal layered on anhydrous MgSO₄ and evaporated todryness. Excess di-t-butyl-dicarbonate and byproduct t-butanol wereremoved by repeated heating with water to 80° C. in vacuo, giving theproduct as a fine white powder (3.11 g, 87%). ¹H-NMR (400 MHz, DMSO-d₆)δ 7.89 (d, J=8.04 Hz, 1H), 7.65 (quartet, J=6.73 Hz, 1H), 7.55 (t,J=6.73 Hz, 1H), 7.34, (dt, J=10.05, 2.51 Hz, 1H), 7.16 (m, 3H), 6.77 (d,J=8.18 Hz, 1H), 5.34 (s, 2H), 4.18 (d, J=5.68 Hz, 2H), 1.34 (s, 9H).¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.26 (quintet, J=6.91 Hz, 1F), −113.53(quartet, J=7.73 Hz, 1F), −120.32 (d, J=8.91 Hz, 2F). LC/MS t_(r)=5.90minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 513(M+H). ES-HRMS m/z 513.1164 (M+H calcd for C₂₄H₂₂ClF₄N₂O₄ requires513.1199).

Step 2: Preparation of the title compound

tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate(from step 3) (1.39 g, 2.71 mmol) was dissolved in 20 ml tetrahydrofuranand treated with 4 ml concentrated hydrochloric acid. The solution wasevaporated and dried in vacuo to a fine white solid (1.20 g, 99%).¹H-NMR (400 MHz, DMSO-d₆) δ 8.54 (m, 2H), 7.86 (d, J=7.57 Hz, 1H), 7.65(quartet, J=7.62, 1H), 7.50 (d, J=9.25 Hz, 2H), 7.34 (dt, J=10.50, 2.45Hz, 1H), 7.16 (dt, J=8.38, 2.55 Hz, 1H), 6.78 (d, J=7.86 Hz, 1H), 5.37(s, 2H), 4.10 (br s, 2H), 4.97-3.14 (v br s, 3H). ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −109.21 (quintet, J=7.77 Hz, 1F), −113.51 (quartet, J=8.95Hz, 1F), −119.56 (d, J=9.44 Hz, 2F). LC/MS t_(r)=4.33 minutes (0-95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 413 (M+H). ES-HRMSm/z 413.0712 (M+H calcd for C₁₉H₁₄ClF₄N₂O₂ requires 413.0674).

Example 345

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(methylamino)methyl]phenyl}pyridin-2(1H)-onehydrochloride Step 1: Preparation of tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl(methyl)carbamate

tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate(from Step 1) (252 mg, 0.491 mmol) and iodomethane (75 mg, 0.528 mmol)are combined in 8 ml anhydrous dimethylformamide. Sodium hydride 60% inmineral oil (30 mg, 0.75 mmol) was added and the mixture stirred undernitrogen at room temperature for 1 hour. Saturated aqueous NH₄Cl wasadded (4 ml) followed by 20 ml water and the product was extracted intoethyl acetate, washed with brine, dried over MgSO₄, filtered, andevaporated to give the product as a white powder (208 mg, 80%). ¹H-NMR(400 MHz, DMSO-d₆) δ 7.87 (d, J=7.85 Hz, 1H), 7.64 (quartet, J=6.66 Hz,1H) 7.32, (dt, J=9.39, 3.29 Hz, 1H), 7.13 (m, 3H), 6.77 (d, J=7.94 Hz,1), 5.38 (s, 2H), 4.43 (s, 2H), 2.90 (s, 3H), 1.40 (br m, 9H) ¹⁹F-NMR(400 MHz, DMSO-d₆) δ −109.25 (quintet, J=8.93 Hz, 1F), −113.53 (quartet,J=9.73 Hz, 1F), −119.89 (d, J=9.35 Hz, 2F). LC/MS t_(r)=6.16 minutes(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes,then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215nm, at 50° C.) ES-MS m/z 527 (M+H). ES-HRMS m/z 527.1338 (M+H calcd forC₂₅H₂₄ClF₄N₂O₄ requires 527.1355).

Step 2: Preparation of the title compound

tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl(methyl)carbamatefrom step 1) (188 mg, 0.357 mmol) was subjected to the conditions ofStep 2, yielding a fine white solid (165 mg, 100%). ¹H-NMR (400 MHz,DMSO-d₆) δ 9.30 (br s, 2H), 7.89 (d, J=7.99 Hz, 1H), 7.65 (quartet,J=7.64, 1H), 7.55 (d, J=8.66 Hz, 2H), 7.34 (dt, J=9.93, 2.57 Hz, 1H),7.17 (dt, J=8.49, 2.48 Hz, 1H), 6.81 (d, J=8.01 Hz, 1H), 5.39 (s, 2H),4.21 (s, 2H), 2.56 (s, 3H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.20(quintet, J=7.56 Hz, 1F), −113.52 (quartet, J=9.67 Hz, 1F), −119.21 (d,J=8.79 Hz, 2F). LC/MS t_(r)=4.30 minutes (0-95% acetonitrile/water,0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at215 nm, at 50° C.) ES-MS m/z 427 (M+H). ES-HRMS m/z 427.0816 (M+H calcdfor C₂₀H₁₆ClF₄N₂O₂ requires 427.0831).

Example 346

3-chloro-1-(4-{[(cyclopropylmethyl)amino]methyl}-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride

The title compound was prepared by direct analogy with replacingiodomethane with bromocyclopropylmethane and extending the reaction timeto 6 hours in Step 1.

Step 1

1 tert-butyl4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl(cyclopropylmethyl)carbamate

¹H-NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=7.91 Hz, 1H), 7.65 (quartet,J=6.81 Hz, 1H), 7.33, (dt, J=9.90, 2.26 Hz, 1H), 7.17 (m, 3H), 6.77 (d,J=7.90 Hz, 1), 5.38 (s, 2H), 4.51 (s, 2H), 3.10 (br s, 2H), 1.36 (m,9H), 0.97 (br s, 1H), 0.38 (m, 2H), 0.18 (m, 2H). ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −109.25 (quintet, J=7.77 Hz, 1F), −113.54 (quartet, J=9.02Hz, 1F), −120.24 (m, 2F). LC/MS t_(r)=5.99 minutes (0 95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95%acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C.) ES-MS m/z 567 (M+H). ES-HRMS m/z 567.1653 (M+H calcd forC₂₈H₂₈ClF₄N₂O₄ requires 567.1668).

Step 2: Title Compound

¹H-NMR (400 MHz, DMSO-d₆) δ 9.51 (br s, 2H), 7.87 (d, J=7.96 Hz, 1H),7.63 (m, 3H), 7.33 (dt, J=9.93, 2.65 Hz, 1H), 7.16 (dt, J=8.36, 2.32 Hz,1H), 6.81 (d, J=7.92 Hz, 1H), 5.38 (s, 2H), 4.22 (br s, 2H), 2.82 (br s,2H), 1.10 (m, 1H), 0.57 (m, 2H), 0.36 (m, 2H). ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −109.25 (quintet, J=7.69 Hz, 1F), −113.54 (quartet, J=9.35Hz, 1F), −120.24 (m, 2F). LC/MS t_(r)=4.55 minutes (0-95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 467 (M+H). ES-HRMSm/z 467.1119 (M+H calcd for C₂₃H₂₀ClF₄N₂O₂ requires 467.1144).

Example 347

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluoro-N,N-dimethylbenzamideStep 1: Preparation of4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzamide

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile(540 mg, 1.32 mmol) and potassium trimethylsilonate 90% (375 mg, 2.63mmol) are combined in 8 ml anhydrous toluene and heated to reflux withstirring. After 10 minutes, the mixture allowed to cool then partitionedbetween saturated aqueous ammonium chloride and ethyl acetate. Theaqueous layer is extracted twice with ethyl acetate, the combinedorganics are washed with brine, dried over MgSO₄, and evaporated invacuo. The crude product is taken up in tetrahydrofuran and filteredthrough charcoal layered over silica gel, and the solution evaporated invacuo to give the product as a white powder (468 mg, 83%). ¹H-NMR (400MHz, DMSO-d₆) δ 8.22 (br s, 2H), 7.92 (d, J=7.84 Hz, 1H), 7.78 (d,J=8.45, 2H), 7.65 (quartet, J=8.40 Hz, 1H), 7.34, (dt, J=10.09, 2.58 Hz,1H), 7.17 (dt, J=8.72, 2.30 Hz, 1H), 6.83 (d, J=7.91 Hz, 1H), 5.39 (s,2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.21 (quintet, J=7.43 Hz, 1F),−113.52 (quartet, J=9.62 Hz, 1F), −118.74 (d, J=8.88 Hz, 2F). LC/MSt_(r)=4.67 minutes (0-95% acetonitrile/water, 0.05% trifluoroaceticacid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/minwith detection at 215 nm, at 50° C.) ES-MS m/z 427 (M+H). ES-HRMS m/z427.0454 (M+H calcd for C₁₉H₁₂ClF₄N₂O₃ requires 427.0467).

Step 2: Preparation of the Title Compound

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzamide(from step 1) (243 mg, 0.357 mmol) was subjected to the conditions ofStep 1, with the exception that two equivalents of sodium hydride 60% inmineral oil and iodomethane were used instead of one (46 mg, 0.69 mmoland 103 mg, 0.724 mmol respectively). ¹H-NMR (400 MHz, DMSO-d₆) δ 7.92(d, J=7.76 Hz, 1H), 7.66 (quartet, J=7.33, 1H), 7.44 (d, J=7.59 Hz, 2H),7.34 (dt, J=9.88, 2.63 Hz, 1H), 7.17 (dt, J=8.35, 2.06 Hz, 1H), 6.83 (d,J=7.55 Hz, 1H), 5.39 (s, 2H), 2.98 (s, 3H), 2.91 (s, 3H). ¹⁹F-NMR (400MHz, DMSO-d₆) δ −109.22 (quintet, J=8.10 Hz, 1F), −113.53 (quartet,J=9.18 Hz, 1F), −118.88 (d, J=7.77 Hz, 2F). LC/MS t_(r)=5.13 minutes(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 455 (M+H).ES-HRMS m/z 455.0791 (M+H calcd for C₂₁H₁₆ClF₄N₂O₃ requires 455.0780).

Example 348

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-methoxybenzonitrileStep 1: Preparation of4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-hydroxybenzonitrile

4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile(522 mg, 1.28 mmol) and potassium trimethylsilonate 90% (655 mg, 4.60mmol) are combined in 8 ml anhydrous tetrahydrofuran and stirred undernitrogen at room temperature for 2 hours. The precipitated potassiumsalt of was collected by filtration, washed with a minimum oftetrahydrofuran, and dried in vacuo. A portion of this salt (275 mg,0.618 mmol) was dissolved in 5 ml water, the pH was adjusted below 6with concentrated hydrochloric acid, the product collected byfiltration, washed with water, sucked dry under a blanket of drynitrogen, and dried further in vacuo overnight (251 mg, 100%, 98%overall). ¹H-NMR (400 MHz, DMSO-d₆) δ 11.46 (br s, 1H), 7.74 (d, J=7.81Hz, 1H), 7.67 (quartet, J=6.76 Hz, 1H), 7.52 (d, J=8.76, 1H), 7.364,(dt, J=10.18, 2.37 Hz, 1H), 7.24 (br s, 1H), 7.17 (br t, J=8.75, 1H),6.74 (d, J=8.04 Hz, 1H), 5.39 (s, 2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ−109.26 (quintet, J=8.50 Hz, 1F), −113.52 (quartet, J=9.29 Hz, 1F),−118.06 (d, J=9.38 Hz, 1F). LC/MS t_(r)=5.13 minutes (0-95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95%acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C.) ES-MS m/z 407 (M+H). ES-HRMS m/z 407.0381 (M+H calcd forC₁₉H₁₁ClF₃N₂O₃ requires 407.0405).

Step 2: Preparation of the Title Compound

The potassium salt of4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-hydroxybenzonitrile(from Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrousdimethylformamide under nitrogen. Iodomethane (93 mg, 0.66 mmol) wasadded, and stirring continued for 2 hr. The mixture was diluted to 50 mlwith ice-cold water, and the white precipitate collected by filtration.The precipitate was washed thrice with water, sucked dry under a blanketof nitrogen, and dried further in vacuo overnight (242 mg, 87%). ¹H-NMR(400 MHz, DMSO-d₆) δ 7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, J=9.90, 2.39Hz, 1H), 7.17 (dt, J=8.75, 2.47 Hz, 1H), 6.75 (d, J=7.97 Hz, 1H), 5.37(s, 2H), 3.84 (s, 3H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.24 (quintet,J=7.85 Hz, 1F), −113.54 (quartet, J=9.83 Hz, 1F), −118.33 (d, J=7.77 Hz,1F). LC/MS t_(r)=5.40 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215nm, at 50° C.) ES-MS m/z 421 (M+H). ES-HRMS m/z 421.0522 (M+H calcd forC₂₀H₁₃ClF₃N₂O₃ requires 421.0561).

Example 349

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}ureaStep 1: Preparation of the Title Compound

1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride (162 mg, 0.361 mmol) is dissolved in 4 ml 50% aqueousacetic acid and treated with potassium cyanate (59 mg, 0.72 mmol). Themixture was stirred 2 hr, then the mixture was diluted to 50 ml withcold water, and the crude product, contaminated with the acetamide, waspurified by silica gel chromatography, eluting first with 20% ethanol inhexane then 40% ethanol in hexane. The 50% fractions were pooled by TLCand evaporated, giving the product as a fine white powder (65 mg, 40%).¹H-NMR (400 MHz, DMSO-d₆) δ 7.87 (d, J=8.07 Hz, 1H), 7.64 (quartet,J=6.53 Hz, 1H), 7.33, (dt, J=9.47, 1.99 Hz, 1H), 7.15 (m, 3H), 6.76 (d,J=7.97 Hz, 1H), 6.59 (m, 1H), 5.65 (br s, 2H), 5.38 (s, 2H), 4.22 (m,2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.22 (quintet, J=7.86 Hz, 1F),−113.51 (quartet, J=9.40 1F), −120.65 (d, J=8.75 Hz, 2). LC/MSt_(r)=4.85 minutes (0-95% acetonitrile/water, 0.05% trifluoroaceticacid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.)ES-MS m/z 456 (M+H).

Example 350

2-({4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}amino)-1,1-dimethyl2-oxoethyl acetate Step 1: Preparation of the Title Compound

1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride (225 mg, 0.501 mmol) is dissolved in a solution of 10 mltetrahydrofuran and triethylamine (111 mg, 1.10 mmol).2-acetoxy-2-methyl-propionyl chloride (85 mg, 0.516 mmol) is added, andthe mixture stirred for 30 minutes before partitioning between saturatedaqueous ammoniom chloride and ethyl acetate. The layers are separated,and the aqueous phase extracted twice with ethyl acetate. The combinedorganics are washed with water and brine, then dried over MgSO₄,filtered, and evaporated in vacuo, giving the product as a fine whitepowder (254 mg, 94%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.47 (t, J=6.16 Hz,1H), 7.88 (d, J=7.71 Hz, 1H), 7.65 (quartet, J=7.24 Hz, 1H), 7.34, (dt,J=10.04, 2.49 Hz, 1H), 7.16 (m, 3H), 6.77 (d, J=7.78 Hz, 1H), 5.38 (s,2H), 4.32 (d, J=5.93 2H), 2.02 (s, 3H), 1.48 (s, 6H). ¹⁹F-NMR (400 MHz,DMSO-d₆) δ −109.26 (quintet, J=9.00 Hz, 1F), 113.52 (quartet, J=9.52 Hz,1F), −120.62 (d, J=9.09 Hz, 2F). LC/MS t_(r)=5.43 minutes (0-95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 541 (M+H). ES-HRMSm/z 541.1128 (M+H calcd for C₂₅H₂₂ClF₄N₂O₅ requires 541.1148).

Example 351

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}acetamide

The compound was prepared in the following the procedure for Example350, substituting acetyl chloride (24 mg, 0.30 mmol) for2-acetoxy-2-methyl-propionyl chloride. (128 mg, 96%). ¹H-NMR (400 MHz,DMSO-d₆) δ 8.48 (br s, 1H), 7.87 (d, J=7.28 Hz, 1H), 7.64 (quartet,J=8.01 Hz, 1H), 7.33, (dt, J=9.87, 2.25 Hz, 1H), 7.17 (m, 3H), 6.76 (d,J=8.25 Hz, 1H), 5.38 (s, 2H), 4.30 (m, 2H), 1.88 (s, 3H). ¹⁹F-NMR (400MHz, DMSO d₆) δ −109.22 (quintet, J=8.04 Hz, 1F), −113.52 (quartet,J=9.91 Hz, 1F), −120.43 (d, J=8.77 Hz, 2F). LC/MS t_(r)=5.04 minutes(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 555 (M+H).ES-HRMS m/z 455.0824 (M+H calcd for C₂₁H₁₆ClF₄N₂O₃ requires 455.0780).

Example 352

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-2-methoxyacetamide

The compound was prepared in the following the procedure for EXAMPLE350, substituting 2-methoxy-acetyl chloride (45 mg, 0.415 mmol) for2-acetoxy-2-methyl-propionyl chloride. (124 mg, 78%). ¹H-NMR (400 MHz,DMSO-d₆) δ 8.56 (t, J=6.77 Hz, 1H), 7.90 (d, J=7.85 Hz, 1H), 7.67(quartet, J=7.67 Hz, 1H), 7.36, (dt, J=10.03, 2.36 Hz, 1H), 7.20 (m,3H), 6.79 (d, J=8.07 Hz, 1H), 5.40 (s, 2H), 4.37 (d, J=6.28 Hz, 2H),3.91 (s, 2H), 3.35 (s, 3H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.23(quintet, J=8.29 Hz, 1F), −113.50 (quartet, J=9.36 Hz, 1F), −120.43 (d,J=9.07 Hz, 2F) LC/MS t_(r)=5.13 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215nm, at 50° C.) ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0856 (M+H calcd forC₂₂H₁₈ClF₄N₂O₄ requires 485.0886).

Example 353

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-2-furamide

The compound was prepared in the following the procedure for EXAMPLE350, substituting furoyl chloride (62 mg, 0.48 mmol) for2-acetoxy-2-methyl-propionyl chloride. Yield: 142 mg, 85%. ¹H-NMR (400MHz, DMSO-d₆) δ 9.07 (t, J=6.14 Hz, 1H), 7.90 (d, J=7.88 Hz, 1H), 7.87(dd, J=1.69, 0.80 Hz, 1H), 7.67 (td, J=8.46, 6.80 Hz, 1H), 7.35, (dt,J=10.00, 2.81 Hz, 1H), 7.26 (d, J=8.78 Hz, 2H), 7.18 (ddt, J=8.58, 2.30,1.07 Hz, 1H), 7.16 (dd, J=3.52, 0.77 Hz, 1H), 6.79 (d, J=8.07 Hz, 1H),6.64 (dd, J=3.16, 1.73 Hz, 1H), 5.40 (s, 2H), 4.49 (d, J=6.13 Hz, 2H).¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.23 (quintet, J=7.65 Hz, 1F), −113.50(quartet, J=9.84 Hz, 1F), −120.29 (d, J=9.41 Hz, 2F). LC/MS t_(r)=5.32minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 507(M+H). ES-HRMS m/z 507.0716 (M+H calcd for C₂₄H₁₆ClF₄N₂O₄ requires507.0729).

Example 354

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-1H-imidazole-4-carboxamideStep 1: Preparation of the Title Compound

1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride (150 mg, 0.334 mmol) is dissolved in a solution of 4 mltetrahydrofuran and triethylamine (35 mg, 0.35 mmol).4-imidazolecarboxylic acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazolehydrate (90 mg, 0.67 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (128 mg,0.668 mmol), and triethylamine (100. mg, 0.989 mmol) were combined in 5ml tetrahydrofuran and stirred under nitrogen. The solution containing1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-onehydrochloride was added in one portion, rinsing with 2 mltetrahydrofuran. Stirring was continued at room temperature overnight,then the reaction was poured into 90 ml of icewater, and the productcollected by filtration and dried in vacuo (254 mg, 94%). ¹H-NMR (400MHz, DMSO-d₆) δ 12.55 (br s, 1H), 8.73 (t, J=6.57 Hz, 1H), 7.90 (d,J=7.87 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 2H), 7.35, (dt, J=10.04, 2.54 Hz,1H), 7.21 (m, 3H), 6.78 (d, J=8.04 Hz, 1H), 5.39 (s, 2H), 4.47 (m, 2H).¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.26 (quintet, J=7.87 Hz, 1F), −113.52(quartet, J=9.30 Hz, 1F), −120.59 (d, J=9.21 Hz, 2F). LC/MS t_(r)=4.48minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 507(M+H). ES-HRMS m/z 507.0818 (M−H calcd for C₂₃H₁₆ClF₄N₄O₃ requires507.0842).

Example 355

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-5-oxoprolinamideStep 1: Preparation of the Title Compound

The compound was prepared following the procedure for Example 354,substituting 2-pyrrolidone-5-carboxylic acid for 4-imidazolecarboxylicacid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.67 (t, J=6.08 Hz, 1H), 7.88 (m, 1H),7.65 (qr, J=7.57, 1H), 7.34, (dt, J=9.32, 2.63 Hz, 1H), 7.22 (d, J=9.36,2H), 7.17 (dt, J=8.51, 2.55 Hz, 1H), 6.77 (d, J=7.66 Hz, 1H), 5.73 (s,1H), 5.38 (s, 2H), 4.35 (d, J=5.74, 2H), 4.05 (m, 1H), 2.15 (m, 2H),1.90 (m, 2H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ −109.25 (quintet, J=7.72 Hz,1F), −113.52 (quartet, J=8.94 Hz, 1F), 120.39 (d, J=9.11 Hz, 2F). LC/MSt_(r)=4.81 minutes (0-95% acetonitrile/water, 0.05% trifluoroaceticacid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.)ES-MS m/z 524 (M+H). ES-HRMS m/z 524.0998 (M+H calcd for C₂₄H₁₉ClF₄N₃O₄requires 524.0995).

Example 356

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-3-hydroxy-3-methylbutanamideStep 1: Preparation of the Title Compound

The compound was prepared following the procedure for substituting2-hydroxy-2-methyl butyric acid for 4-imidazolecarboxylic acid. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.43 (t, J=6.04 Hz, 1H), 7.88 (d, J=8.01, 1H), 7.65(qr, J=6.84, 1H), 7.34, (dt, J=10.13, 2.55 Hz, 1H), 7.22 (d, J=8.74,2H), 7.16 (dt, J=8.57, 2.45 Hz, 1H), 6.77 (d, J=7.89 Hz, 1H), 5.38 (s,2H), 4.75 (s, 0.5H(OH), 4.35 (d, J=6.48, 2H), 2.28 (s, 2H), 1.47 (s,0.5H(OH), 1.16 (s, 6H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.26 (quintet,J=7.79 Hz, 1F), −113.53 (quartet, J=9.23 Hz, 1F), −120.49 (d, J=9.39 Hz,2F). LC/MS t_(r)=5.08 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215nm, at 50° C.) ES-MS m/z 513 (M+H). ES-HRMS m/z 513.1177 (M+H calcd forC₂₄H₂₂ClF₄N₂O₄ requires 513.1199).

Example 357

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-1-hydroxycyclopropanecarboxamideStep 1: Preparation of the Title Compound

The compound was prepared following the procedure for substituting1-hydroxy-1-cyclopropanecarboxylic acid for 4-imidazolecarboxylic acid.¹H-NMR (400 MHz, DMSO-d₆) δ 8.70 (t, J=6.26 Hz, 1H), 7.89 (d, J=6.31,1H), 7.65 (qr, J=6.83, 1H), 7.34 (t, J=10.58 Hz, 1H), 7.19 (m, 3H), 6.77(d, J=7.70 Hz, 1H), 5.38 (s, 2H), 4.35 (d, J=5.66, 2H), 1.14 (s, 1H),1.02 (m, 2H), 0.84 (m, 2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.25(quintet, J=8.05 Hz, 1F), −113.53 (quartet, J=8.27 Hz, 1F), −120.59 (d,J=8.99 Hz, 2F). LC/MS t_(r)=5.01 minutes (0-95% acetonitrile/water,0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at215 nm, at 50° C.) ES-MS m/z 497 (M+H). ES-HRMS m/z 497.0873 (M+H calcdfor C₂₃H₁₈ClF₄N₂O₄ requires 497.0886).

Example 358

N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzyl}-2-hydroxy-2-methylpropanamideStep 1: Preparation of the Title Compound

The compound was prepared following the procedure for substituting2-hydroxyisobutyric acid for 4-imidazolecarboxylic acid. ¹H-NMR (400MHz, DMSO-d₆) δ 8.48 (t, J=6.41 Hz, 1H), 7.89 (d, J=7.78, 1H), 7.65 (qr,J=9.10, 1H), 7.33 (dt, J=10.12, 2.41 Hz, 1H), 7.17 (m, 3H), 6.77 (d,J=7.69 Hz, 1H), 5.38 (s, 2H), 4.31 (d, J=6.50, 2H), 1.41 (s, 1H), 1.33(s, 6H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.25 (quintet, J=7.49 Hz, 1F),−113.53 (quartet, J=9.64 Hz, 1F), −120.59 (d, J=8.68 Hz, 2F). LC/MSt_(r)=5.05 minutes (0-95% acetonitrile/water, 0.05% trifluoroaceticacid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ESMS m/z 499 (M+H). ES-HRMS m/z 499.1020 (M+H calcd for C₂₃H₂₀ClF₄N₂O₄requires 499.1042).

Example 359

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrileStep 1: Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one

The compound was prepared in the following the procedure for3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one (, Step 3),substituting N-bromosuccinimide for N-chlorosuccinimide. ¹H-NMR (400MHz, DMSO-d₆) δ 11.85 (br s, 1H), 7.61 (m, 1H), 7.46 (d, J=7.36 Hz, 1H),7.30, (m, 1H), 7.14 (m, 1H), 6.40 (d, J=7.71 Hz, 1H), 5.26 (s, 2H).¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.69 (quintet, J=7.93 Hz, 1F), −113.63(quartet, J=9.55 Hz, 1F). LC/MS t_(r)=4.48 minutes (0-95%acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 316 (M+H).

Step 2: Preparation of the Title Compound

The compound was prepared following the procedure for4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile(, Step 4), substituting3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one (from step 1) (1.92g, 6.06 mmol) for 3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one(, from Step 3). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.13 d, J=7.24 Hz, 2H),7.95 (d, J=7.76 Hz, 1H), 7.66 (quartet, J=8.71 Hz, 1H), 7.34, (dt,J=9.94, 2.53 Hz, 1H), 7.17 (dt, J=8.64, 2.33 Hz, 1H), 6.82 (d, J=7.77Hz, 1H), 5.39 (s, 2H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.28 (quintet,J=7.98 Hz, 1F), −113.45 (quartet, J=9.29 Hz, 1F), −116.30 (d, J=7.44 Hz,2F). LC/MS t_(r)=5.48 minutes (0-95% acetonitrile/water, 0.05%trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215nm, at 50° C.) ES-MS m/z 453 (M+H). ES-HRMS m/z 452.9836 (M+H calcd forC₁₉H₁₀BrF₄N₂O₂ requires 452.9856).

Example 360

3-Bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-oneStep 1: Preparation of1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15.0 mL) was heatedto reflux for 16 h under argon atmosphere. Butanol wad distilled invacuo, the residue was triturated with EtOAc, cooled and filtered theprecipitate. It was washed with cold EtOAc, and dried to give 0.86 g ofthe title compound as a pale yellow powder: 1H-NMR (CD₃OD/400 MHz) δ7.31 (m, 1H), 7.0-6.85 (m, 2H), 6.83 (d, 1H, J=9.6 Hz), 5.96 (d, 1H,j=2.0 Hz), 5.80 (d, 1H, J=2.0 Hz), 5.30 (s, 2H), and 2.24 (s, 3H); ESMSm/z 234 (MH⁺).

Step 2: Preparation of3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.8g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL)was stirred at room temperature, under argon atmosphere. After 1.5 h,the reaction mixture was diluted with dichloromethane (15.0 mL), cooledand filtered the solids. The residue was washed with dichloromethane anddried in vacuo to give 0.93 g of the title compound as a white powder:1H-NMR (CD₃OD/400 MHz) δ 7.33 (m, 1H), 7.2-6.8 (m, 3H), 6.07 (s, 1H),5.34 (s, 2H), 2.26 (s, 3H); ESHRMS m/z 312.0016 (M+H C13H12NO2BrFrequires 312.0035).

Step 3: Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a suspension of3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one

(0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to −30° C.,triethyl amine (0.5 mL, 0.004 mol) and trflic anhydride (0.7 mL, 0.0042mol) were added and stirred for 1 h. The resulting orange solution waspoured into ice cold water (25 mL) and extracted with dichloromethane(2×25 mL) The combined organic extracts were washed with water, dried(Na2SO4) and concentrated under reduced pressure. The resulting residuewas purified by silica gel flash chromatography using 1:1 EtOAc/hexanev/v to afford 1.0 g (85%) the title compound as a light brown solid:¹H-NMR (CDCl3/400 MHz) δ

7.32 (m, 1H), 7.0-6.85 (m, 3H), 6.18 (s, 1H), 5.32 (s, 2H), and 2.34 (s,3H); ESHRMS m/z 443.9492 (M+H C14H11NO4BrF4S requires 443.9528).

Step 4: Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one

A solution of3-bromo-1-(3-fluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.0 g, 0.0022 mol) and phenylacetylene (0.3mL, 0.0029 mol) in DMF (5.0 mL) was degassed using house vacuum, andpurged with argon (3 cycles).

Then added diisopropylethylamine, (0.5 mL) followed by the addition ofPdCl2(PPh3)₂ (0.36 g). The reaction mixture was heated at 65° C. for 1.5h under argon atmosphere. The solvents were distilled in vacuo, and theresidue was purified by silica gel flash chromatography usingEtOAc/hexane (2:3 v/v) to afford 0.65 g (70%) of the title compound as abrown colored amorphous solid: ¹H-NMR (CD₃OD/400 MHz). δ7.59 (m, 2H),7.45-7.3 (m, 4H), 7.05-6.85 (m, 3H), 6.44 (s, 1H), 5.41 (s, 2H), and2.31 (s, 3H); ¹⁹F-NMR (CD₃OD/400 MHz) δ −116.33 (m); ESHRMS m/z 396.0373(M+H C₂₁H₁₆NOBrF 396.0399).

Step 5: Preparation of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(1H)-one

To a solution of3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one(0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was addedPtO2 (0.05 g) and stirred in an atmosphere of hydrogen gas at 15 psi for30 min. The catalyst was removed by filtration, the filtrate wasconcentrated and the residue was purified by silica gel flashchromatography using 25% EtOAc in hexane as the eluent.

The appropriate fractions were combined (visualized under UV) andconcentrated to dryness. ¹H-NMR (CD₃OD/400 MHz) δ 7.35 (m, 1H),7.31-7.16 (m, 5H), 6.99 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 6.20 (s,1H), 5.41 (s, 2H), 2.94 (m, 4H), and 224 (s, 3H); ¹⁹F-NMR (CD₃OD/400MHz) δ −115.01 (m); ESHRMS m/z 400.0695 (M+H C21H20NOBrF 400.0712).

Example 361

3-bromo-1-(3-fluorobenzyl)-4-(1-phenylethoxy)pyridin-2(1H)-one

A mixture of 3-bromo-1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (0.2g, 0.72 mmol), potassium carbonate (0.1 g, 0.72 mmol) and(1-bromoethyl)benzene (0.19 g, 1 mmol) in DMF (3.0 mL) was stirred atroom temperature for 16 h. DMF was distilled in vacuo, and the residuewas purified by flash chromatography (EtOAc in hexane (1:3 v/v) to givepale yellow syrup. This material was further purified by reverse-phaseHPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of100 mL/min. The appropriate fractions were combined, concentrated to asmall volume (20 mL), added EtOAc (25 mL) and washed successively withsatd. sod. bicarbonate, water, and dried (Na₂SO₄). EtOAc was removedunder reduced pressure and residue was dried in vacuo to afford thetitle compound (0.15 g, 52%) as an amorphous substance: ¹H NMR(CD₃OD/400 MHz) δ 7.56 (d, 1H, J=7.6 Hz), 7.4-7.2 (m, 5H), 7.0 (m, 3H),6.28 (d, 1H, J=7.6 Hz), 5.65 (m, 1H), 5.19 (d×d, 2H, J=14.8 Hz), and1.64 (d, 3H, J=6.4 Hz), ES-HRMS m/z 402.0492 (M+H C₂₀H₁₈NO₂Br, requires402.0499).

Example 362

3-bromo-1-(3-fluorobenzyl)-4-[(E)-2-(4-fluorophenyl)ethenyl]pyridin-2(1H)-one

A mixture of 3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.0 g, 0.0023 mol), and 4-fluorostyrene (0.33mL, 0.0028 mol) in degassed DMF (10 0 ml) containing diisopropyl ethylamine (0.37 g, 0.0029 mol) was treated with PdCl₂(PPh₃)₂ (0.32 g, 0.46mmol) and heated at 65° C. under argon atmosphere for 16 h. DMF wasdistilled in vacuo, and the residue was purified by flash chromatography(EtOAc/hexane 1:4 v/v) to afford a yellow substance which was furtherpurified by reverse-phase HPLC using 10-90% acetonitrile/water gradient(30 min), at flow rate of 100 mL/min. The appropriate fractions werecombined, concentrated to a small volume (20 mL), added EtOAc (25 mL)and washed successively with satd. sod. bicarbonate, water, and dried(Na₂SO₄). ELOAc was removed under reduced pressure and residue was driedin vacuo to afford the title compound (0.06 g, 6%) as yellow powder: ¹HNMR (CD₃OD/400 MHz) δ 7.68 (m, 3H), 7.39 (m, 3H), 7.2-7.0 (m, 5H), 6.82(d, 1H, J=7.2 Hz), and 5 22 (s, 2H); ¹⁹F NMR (CD₃OD/400 MHz) δ −113.9(m) and −115 (m); ES-HRMS m/z 402.0305 (M+HC₂₀H₁₅NOF₂Br, requires402.0300).

Example 363

4-(Benzyloxy)-3-bromo-1-[(6-fluoropyridin-3-yl)methyl]pyridin-2(1H)-one

A mixture of 4-(benzyloxy)-3-bromopyridin-2(1H)-one (0.2 g, 0.00076mol), 5-bromomethyl-2-fluoropyridine (0.25 g, 0.0013 mol) and pot.Carbonate (0.15 g, 0.0011 mol) in DMF (3.0 ml) was stirred at roomtemperature for 16 h under argon atmosphere. DMF was distilled in vacuoand the residue was partitioned between water (15 ml) and EtOAc (25 mL).The organic phase was washed with water, dried (Na₂SO₄) and concentratedunder reduced pressure. ¹H NMR (CD₃OD/400 MHz) δ 8.22 (m, 1H, 2.4 Hz),7.92 (m, 1H), 7.82 (d, 1H, J=7.6 Hz), 7.44-7.31 (m 5H), 7.03 (m, 1H)6.49 (d, 1H, J=7.6 Hz), 5.29 (s, 2H), and 5.20 (s, 2H); ¹⁹F NMR(CD₃OD/400 MHz)_(6-72.30) (d, J=6.0 Hz) and −115 (m); ES-HRMS m/z389.0295 (M+H C₁₈H₁₅N₂O₂FBr, requires 389.0309).

Example 364

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-oneStep 1 Preparation of

1-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol), 2,6dimethylaniline (2.4 g, 0.02 mol), and p-toluenesulfonic acid (0.2 g) asheated at 140° C. for 3 h under nitrogen atmosphere. The reactionmixture was cooled, triturated with acetonitrile, cooled and filteredthe solids.

¹H NMR (CD₃OD/400 MHz) δ 7.22 (m, 3H), 6.12 (d, 1H, J=1.6 Hz), 5.83 (d,1H, J=1.8 Hz), 2.00 (s, 6H), and 1.82 (s, 3H); ESMS m/z 229 (M+H).

Step 2 Preparation of

3-Bromo-1-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 1-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one(0.4 g, 0.00175 mol), and NBS (0.35 g, 0.0019 mol) in dichloromethane(10.0 ml) was stirred at room temperature under nitrogen atmosphere.After 1 h, the solids were filtered, washed with dicholoromethane togive 0.42 g (78%) of the title compd as a pale yellow powder: ¹H NMR(CD₃OD/400 MHz) δ 7.22 (m, 3H), 6.21 (s, 1H), 1.99 (s, 6H), and 1.82 (s,3H); ESMS m/z 308/310 (M+H).

Step 3

A mixture of3-Bromo-1-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.15g, 0.00049 mol), 2,4 difluorobenzyl bromide (0.12 g, 0.00058 mol) andpotassium carbonate (0.075 g, 0.00054 mol) in DMF 3.00 mL) was stirredat room temperature uder argon atmosphere for 2 h. It was then heated at60° C. for 30 min and concentrated in vacuo. The residue was purified byflash chromatography. ¹H NMR (CD₃OD/400 MHz) δ 7.62 (m, 1H), 7.28 (m,3H), 7.04 (m, 2H), 6.68 (s, 1H), 5.35 (m, 1H), 1.98 (s, 6H), and 1.92(s, 3H); ES-HRMS m/z 434.0574 (M+H C₂₁H₁₉NO₂F₂Br, requires 434.0562).

Example 365

3-Bromo-1-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for Example 364. ¹H NMR (CD₃OD/400 MHz) δ 7.58 (m, 2H), 7.23(m, 3H), 7.15 (m, 2H), 6.62 (s, 1H), 5.32 (s, 2H), 1.98 (m, 6H), and1.91 (s, 3H); ES-HRMS m/z 416.0670. (M+H C₂₁H₂₀NO₂FBr, requires416.0656).

Example 366

3-Bromo-1-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 364. ¹H NMR (CD₃OD/400 MHz) δ 7.19 (m, 3H), 6.95(m, 2H), 6.69 (s, 1H), 5.29 (s, 2H), 1.95 (s, 6H), and 1.90 (s, 3H);ES-HRMS m/z 452.0471. (M+H C₂₁H₁₈NO₂F₃Br, requires 452.0468).

Example 367

3-Bromo-4-[(2,6-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 364. ¹H NMR (CD₃OD/400 MHz) δ 7.46 (m, 1H), 7.24(m, 3H), 7.08 (m, 2H), 6.74 (s, 1H), 5.38 (s, 2H), 1.99 (s, 6H), and1.94 (s, 3H); ES-HRMS m/z 434.0589 (M+H C₂₁H₁₉NO₂F₂Br, requires434.0562).

Example 368

3-Bromo1-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1 Preparation of1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedin step 1 for EXAMPLE 364. Yield: 28%, ¹H NMR (CD3OD) δ7.6 (m, 2H), 7.48(m, 1H), 6.10 (dd, 1H), 5.78 (d, 1H, J=2.4 Hz), 1.91 (s, 3H); (ES-MSm/z=270 (MH⁺);

Step 2 Preparation of3-bromo-1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedin step 2 for EXAMPLE 364. Yield: 78%, ¹H NMR (400 MHz) CD₃OD δ7.61 (m,2H), 7.49 (m, 1H), 6.2 (s, 1H), and 1.91 (s, 3H); ES-MS, m/z=348 (MH⁺).

Step 3

This compound was prepared by a procedure similar to the one describedin step 3 for EXAMPLE 364. Yield: 44%, ¹H NMR (CD₃OD) δ7.62 (d, 2H,J=8.0 Hz), 7.51 (m, 3H), 7.15 (m, 2H), 6.64 (s, 1H), 5.33 (s, 2H), and2.0 (s, 3H); ¹⁹F NMR (CD₃OD) δ −166.21 (m); ES-HRMS m/z 455.9541 (M+HC₁₉H₁₄NO₂Cl₂BrF, requires 455.9564).

Example 369

3-Bromo-1-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedfor EXAMPLE 368.

Yield: 64%, ¹H NMR (CD₃OD/400 MHz δ7.62 (m, 3H), 7.48 (m, 1H), 7.05 (m,2H), 6.70 (s, 1H), 5.36 (s, 2H), and 2.02 (s, 3H), ¹⁹F NMR (CD₃OD) δ−111.43 (m) and −115.89 (m); ES-HRMS m/z 473.9450 (M+H C₁₉H₁₃NO₂Cl₂BrF₂,requires 473.9469).

Example 370

3-Bromo-1-(2,6-dichlorophenyl)-4-[(2,6-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedfor EXAMPLE 368. Yield: 78%, ¹H NMR (CD₃OD/400 MHz) δ7.62 (d, 2H, J=8.0Hz), 7.52 (m, 2H), 7.1 (m, 2H), 6.77 (s, 1H), and 2.04 (s, 3H); ¹⁹F NMR(CD₃OD) δ −117.04 (m); ES-HRMS m/z 473.9468 (M+H C₁₉H₁₃NO₂Cl₂BrF₂,requires 473.9469).

Example 371

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-oneStep 1 Preparation of4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedin step 1 for EXAMPLE 368. Yield: 21%, ¹H NMR (CD₃OD/400 MHz) δ7.31 (m,1H), 6.94 (m, 2H), 6.05 (d, 1H, J=2.4 Hz), 5.78 (d, 1H, J=2.4 Hz), 3.76(s, 3H), 2.00 (s, 3H), and 1.83 (s, 3H); ES-HRMS m/z 246.1092 (M+HC₁₄H₁₆NO₃, requires 246.1123).

Step 2 Preparation of3-bromo-4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-methylpyridin-2(1H)-one

This compound was prepared by a procedure similar to the one describedin step 2 for EXAMPLE 368. Yield: 58%, ¹H NMR (CD₃OD/400 MHz) δ7.34 (m,1H), 6.96 m (2H), 6.15 (s, 1H), 3.76 (s, 3H), 1.99 (s, 3H), and 1.83 (s,3H); ESMS m/z 324 (M+H).

Step 3

This compound was prepared by a procedure similar to the one describedfor EXAMPLE 368. Yield: 60%, ¹H NMR (CD₃OD/400 MHz) 67.63 (m, 1H), 7.36(m, 1H), 7.01 (m, 4H), 6.61 (s, 1H), 5.33 (s, 2H), 3.76 (s, 3H), 1.99(s, 3H), and 1.95 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −111.64 (m), and−116.03 (m); ES-HRMS m/z 450.0532 (M+H C₂₁H₁₉NO₃Cl₂BrF₂, requires450.0511).

Example 372

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-dichlorobenzenesulfonamideStep 1 Preparation of3,5-dichloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzenesulfonamide

A mixture of 4-hydroxy-6-methylpyrone ((1.2 g, 0.0095 mol), and2,6-dichlorosulphanilamide (2.4 g, 0.0099 mol) was heated at 170° C.under argon for 20 min. The resulting dark colored melt was cooled andthe crude material was first purified by flash chromatography (EtOAc) togive partially purified material which contained the desired product.This was further purified by reverse-phase HPLC using 10-90% CH₃CN/Water(30 min gradient) at a flow rate of 100 mL/min. The appropriatefractions (m/z 349)were combined and freeze dried to afford 0.19 g of3,5-dichloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzenesulfonamideas pale yellow solid: ¹H NMR (CD₃OD/400 MHz) δ8.06 (s, 2H), 6.13 (d, 1H,J=1.6 Hz), 5.78 (d, 1H, J=1.6 Hz), and 1.94 (s, 3H)); ES-HRMS m/z348.9819 (M+H C₁₂H₁₁N₂O₄SCl₂ requires 348.9811).

Step 2

A mixture of3,5-dichloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzenesulfonamide(0.18 g, 0.0005 mol), N-bromosuccinimide (0.1 g, 0.00056 mol)in aceticiacid (2.0 mL) was stirred at room temperature under argon atmosphere for1 h. Acetic acid was removed in vacuo, the residue was dissolved in DMF(2.0 mL), and added 2,4-difluorobenzyl bromide (0.128 g, 0.0006 mol),potassium carbonate (0.1 g, 0.0007 mol). The resulting mixture wasstirred at room temperature for 1 h. The solvents were distilled invacuo, and the residue was purified by flash chromatography(EtOAc/hexane 1:3 v/v) to give 0.14 g of partially purified product.This was further purified by reverse-phase HPLC using 10-90% CH₃CN/Water(30 min gradient) at a flow rate of 100 mL/min. The appropriatefractions (m/z 553) were combined and freeze dried to afford 0.045 g ofpale yellow powder. This was partitioned between EtOAc (25 ml) and 5%sod. bicarbonate. The organic phase was washed with water, dried(Na₂SO₄) and concentrated under reduced pressure. This material wasdried invacuo to afford the title compound (0.033 g) as a whiteamorphous substance:

¹H NMR (CDCl₃/400 MHz) δ7.99 (s, 2H), 7.59 (m, 1H), 6.98 (m, 1H), 6.85(m, 1H), 6.23 (s, 1H), 5.69 (s, 2H), 5.28 (s, 2H), 1.97 (s, 3H), and1.76 (br, 2H); ES-HRMS m/z 552.7214 (M+H C₁₉H₁₄BrCl₂N₂O₄S requires552.9197).

Example 373

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-oneStep 1 Preparation of1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6difluoroaniline (9.5 g, 0.073 mol) was heated at 170° C. under argonatmosphere for 20 min. The water formed was removed using a Dean-starkapparatus. The melt was cooled, the dark solid was tritutrated withEtOAc., and filtered. This material was washed thoroughly with EtOAc toafford the desired product1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 6.5 g (35%)as a light brown solid: ¹H NMR (CD₃OD/400 MHz) δ7.56 (m, 1H), 7.19 (m,2H), 6.09 (m, 1H), 5.77 (d, 1H, J=2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z238.0679 (M+H C₁₂H₁₀NO₂F₂ requires 238.0674).

Step 2 Preparation of3-bromo-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure described in step 2 forEXAMPLE 364.

Yield: 79%, ¹H NMR (CD₃OD/400 MHz) δ7.58 (m, 1H), 7.21 (m, 2H), 6.19 (d,1H, J=0.8 Hz), 1.99 (s, 3H); ES-HRMS m/z 315.9811 (M+H C₁₂H₉NO₂F₂Brrequires 315.9779).

Step 3

This compound was prepared by a procedure described in step 3 forEXAMPLE 364.

Yield: 63%, ¹H NMR (CD₃OD) δ 7.58 (m, 2H), 7.23 (m, 2H), 7.06 (m, 2H),6.68 (s, 1H), 5.36 (s, 2H), and 2.10 (s, 3H); ¹⁹F NMR (CD₃OD) δ −111.50(m), −115.96 (m), and −121.93 (m); ES-HRMS m/z 442.0061 (M+HC₁₉H₁₃NO₂F₄Br requires 442.0060).

Example 374

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

A solution of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one(0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) indichloroethane, containing dichloroacetic acid (0.1 mL) was heated toreflux for 6 h under argon atmosphere. After the removal of the solventsunder reduced pressure, the residue was partitioned between,dichloromethane (20 mL) and 5% sod. sulphite (10 mL). The organic phasewas washed with water, dried (Na₂SO₄), and concentrated under reducedpressure. The residue was purified by flash chromatography (25% EtOAc inhexane) to afford the title compound (0.125 g, 32%) as a pale yellowpowder: ¹H NMR (CDCl₃/400 MHz) δ7.68 (m, 1H), 7.46 (m, 1H), 7.11 (m,2H), 6.95 (m, 1H), 6.85 (m, 1H), 5.23 (s, 2H), and 2.38 (s, 3H); ¹⁹F NMR(CDCl₃) δ −109.15 (m), −112.95 (m), −118.50 (m); ES-HRMS m/z 567.9014(M+H C₁₉H₁₂NO₂F₄BrI requires 567.9027).

Example 375

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(1H)-oneStep 1

3,5-difluoro N˜1˜,N˜-1˜-dimethylbenzene-1,2-diamine

To a solution of 2,4,6-trifluoronitrobenzene (2.58 g, 0.0145 mol) in THF(20.0 ml) was added a solution of N,N-dimethylamine in THF (8.5 mL of 2Msoln) and stirred for 45 min at 0° C. It was then stirred at roomtemperature for 30 min and concentrated to dryness. The resultingmaterial was dissolved in EtOH (25 mL), added Pd/C (10%, 0.6 g) andhydrogenated at 50 psi for 4 h. The catalyst was removed by filtration,and the filtrate was concentrated to dryness under reduced pressure. Theresidue was partitioned between sod. bicarbonate (10%, 25 mL) and EtOAc(30 mL). The organic phase was washed with water, dried (Na₂SO₄), andconcentrated to dryness to afford the title compound (1.3 g, 50%) as adark colored solid: ¹H NMR (CDCl₃/400 MHz) δ6.52 (m, 2H), 3.64 (br, 2H),and 2.65 (s, 6H); ES-HRMS m/z 172.0772 (M+C₈H₁₀N₂F₂ requires 172.0810).

Step 2

1-[2-(dimethylamino)-4,6-difluorophenyl]-4-hydroxy-6-methylpyridin-2(1H)-one

An intimate mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g, 0.0103 mol),and 3,5-difluoro-N,N-dimethylbenzene-1,2-diamine (1.4 g, 0.008 mol) washeated at 160° C. under argon for 15 min. The dark colored reactionmixture was cooled, triturated with EtOAc (15 ml), and filtered. Thesolids were washed with warm EtOAc, followed by hexane and dried to givethe title compound as a light blue solid (0.4 g, 14%). Analytically puresample was prepared by reverse-phase HPLC purification using 10-90%CH₃CN/Water (30 min gradient) at a flow rate of 100 mL/min. Theappropriate fractions were combined and freeze-dried to give the titlecompound: ¹H NMR (CD₃OD/400 MHz) δ 6.61 (m, 2H), 6.08 (d, 1H, J=2.0 Hz),δ 78 (d, 1H, J=2.0 Hz), 2.69 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z281.1084 (M+H C₁₄H₁₅N₂O₂F₂ requires 281.1096).

Step 2 Preparation of

3-bromo-1-[2-(dimethylamino)-4,6-difluorophenyl]-4-hydroxy-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure described in step 2 forEXAMPLE 364. Yield: 71%, ¹H NMR (CD₃OD/400 MHz) δ6.62 (m, 2H), 6.17 (s,1H), 2.67 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 359.0188 (M+HC₁₄H₁₄N₂O₂F₂Br requires 359.0201).

Step 3

This compound was prepared by a procedure described in step 3 forEXAMPLE 364.

Yield: 34%, ¹H NMR (CDCl₃/400 MHz) δ7.62 (m, 1H), 6.98 (m, 1H), 6.85 (m,1H), 6.46 (m, 2H), 6.11 (s, 1H), 5.24 (s, 2H), 2.66 (s, 6H), and 1.98(s, 3H); ¹⁹F NMR (CDCl₃/400 MHz) δ −108 06 (m), −109.60 (m), −115.02(m), and −116.01 (m); ES-HRMS m/z 485.0451 (M+H C₂₁H₁₈N₂O₂F₄Br requires485.0482).

The title compound was prepared by stirring a suspension of the productof step 3, above, (0.14 g) with 4N HCl in dioxane (0.7 mL) at roomtemperature for 30 min. The mixture was concentrated to dryness. ¹H NMR(CD₃OD/400 MHz) δ7.62 (m, 1H), 7.02 (m, 2H), 6.65 (m, 3H), 5.34 (s, 2H),2.66 (s, 6H), and 2.05 (s, 3H); ESMS m/z=485.

Example 376

3-Bromo4-[(2,4-difluorobenzyl)oxy]-1-{2,4-difluoro-6-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-one

The title compound was prepared by a similar procedure described forEXAMPLE 375, replacing N,N-dimethyl group by N-Methyl-aminoethanol. ¹HNMR (CDCl₃/400 MHz) δ7.59 (m, 1H), 6.98 (m, 1H), 6.85 (m, 1H), 6.61 (m,1H), 6.52 (m, 1H), 6.17 (m, 1H), 5.25 (s, 2H), 3.63 (m, 1H), 3.53 (m,1H), 3.26 (m, 1H), 3.0 (m, 1H), 2.66 (s, 6H), and 2.09 (s, 3H); ES-HRMSm/z 515.0512 (M+H C₂₂H₂₀N₂O₃F₄Br requires 515.0588).

Example 377

2-({[3-Bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrileStep 1

2-(Bromomethyl)-5-fluorobenzonitrile

A mixture of 5-fluoro-2-methylbenzonitrile (2.0 g, 0.015 mol), NBS (3.2g, 0.018 mol) and benzoylperoxide (0.25 g) in carbontetrachloride (25.0ml) was heated to reflux for 6 h, under argon atmosphere. The reactionmixture was cooled and filtered. The filtrate was concentrated underreduced pressure, and the residue was purified by flash chromatography(5% EtOAc in hexane) to afford 2-(Bromomethyl)-5-fluorobenzonitrile (1.9g, 60%) as a colorless liquid: ¹H NMR (CDCl₃/400 MHz) δ7.59 (m) 7.58 (m,1H), 7.38 (m, 1H), and 7.25 (m, 1H).

Step 2

A mixture of3-bromo-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

-   1.0 g, 0.0032 mol), potassium carbonate (0.65 g, 0.0047 mol) and    2-(Bromomethyl)

5-fluorobenzonitrile (0.95 g, 0.0045 mol) in dimethylacetamide (15.0 ml)was stirred at room temperature under argon atmosphere. After 1 h,dimethylacetamide was distilled in vacuo and the residue was partitionedbetween dichloromethane (50 ml) and 55 citric acid (15 mL). The organicphase was washed with water, dried (Na₂SO₄), and concentrated todryness. The resulting material was triturated with EtOAc, filtered,washed with EtOAc and dried to afford the title compound (0.86 g, 60%)as a white powder: ¹H NMR (DMSO-d₆/400 MHz) δ7.95 (m, 1H), 7.81 (m, 1H),7.68 (m, 2H), 7.37 (m, 2H), 6.79 (s, 1H), 5.45 (s, 2H), and 2.03 (s,3H); ¹⁹F-NMR (DMSO-d₆) δ −111.31 (m), −120.34 (m); ES-HRMS m/z 449.0094(M+H C₂₀H₁₃N₂O₂F₃Br requires 449.0107).

Example 378

4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate

To a cold suspension of2-({[3-Bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile(0.3 g, 0.00066 mol) in THF (3.0 mL), was added BH₃.THF (1.0 mL). Afterstirring at room temperature for 15 min, the reaction mixture was heatedto reflux for 30 min under argon atmosphere. The resulting clearsolution cooled, added MeOH (2.0 mL), concentrated under reducedpressure, and the residue was purified by reverse-phase HPLCpurification using 10-90% CH₃CN/Water (30 min gradient) at a flow rateof 100 mL/min. The appropriate fractions (m/z=453 M+H) were combined andfreeze-dried to give the title compound (0.16 g, 43%) as itstrifluoroacetate salt: ¹H NMR (DMSO-d₆/400 MHz) δ8.19 (br, 3H), 7.65 (m,2H), 7.37 (m, 4H), 6.78 (s, 1H), 5.42 (s, 2H), 4.21 (br, 2H), and 2.04(s, 3H); ¹⁹F NMR (DMSO-d₆/400 MHz) δ −112.96 (m), and −120.41 (m);ES-HRMS m/z 453.0387 (M+H C₂₀H₁₇N₂O₃F₃Br requires 453.0420).

Example 379

N-[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]urea

To a suspension of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.13 g, 0.00023 mol) in THF (3.0 mL), was addedtriethyl amine (0.07 mL, 0.0005 mol) followed by the addition oftrimethylsilylisocyanate (0.066 mL). The reaction mixture was stirred atroom temperature for 1 h, and the desired product was isolated byreverse-phase HPLC purification using 10-90% CH₃CN/Water (30 mingradient) at a flow rate of

100 mL/min. The appropriate fractions (m/z=496 M+H) were combined andfreeze-dried, and the residue was partitioned between 5% sod.bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase waswashed with water, dried (Na₂SO₄) and concentrated to dryness underreduced pressure, to afford the title compound as a white amorphouspowder (0.065 g): ¹H NMR (DMSO-d₆/400 MHz) δ7.62 (m, 1H), 7.52 (m, 1H),7.35 (m, 2H), 7.09 (m, 2H), 6.77 (s, 1H), 6.51 (t, 1H), 5.61 (s, 2H),5.38 (s. 2H), 4.28 (d, 2H, J=6.0 Hz), and 2.02 (s, 3H); ¹⁹F NMR(DMSO-d₆/400 MHz) δ −114.044 (m), and −120.31 (m); ES-HRMS m/z 496.0460(M+H C₂₁H₁₈N₃O₃F₃Br requires 496.0478).

Example 380

Methyl2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

To solution of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.12 g, 0.00021 mol) in dimethylacetamide (2.0 mL) at0° C., was added triethylamine (0.06 mL, 0.00043 mol) followed by theaddition of methylchloroformate (0.05 mL). The reaction mixture wasstirred at room temperature for 30 min under argon atmosphere.Dimethylacetamide was distilled in vacuo and the residue was partitionedbetween dichloromethane (10 mL) and 5% citric acid (10 mL). The organicphase was washed with water, dried (Na₂SO₄) and concentrated to dryness.The resulting residue was purified by flash chromatography (60% EtOAc inhexane) to afford the title compound (0.09 g, 75%) as a white amorphouspowder: ¹H NMR (DMSO-d₆/400 MHz) δ7.68 (m, 1H), 7.62 (m, 1H), 7.59 (m,1H), 7.38 (m, 2H), 7.115 (m, 2H), 6.78 (s, 1H), 5.38 (s, 2H), 4.31 (d,2H, J=6.0 Hz), 3.53 (s, 3H), and 2.03 (s, 3H); ¹⁹F NMR (DMSO-d₆/400 MHz)δ 113.77 (m), and −120.33 (m); ES-HRMS m/z 511.0508 (M+H C₂₂H₁₉N₂O₄F₃Brrequires 511.0475).

Example 381

N-[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]-2-hydroxyacetamide

To a suspension of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.12 g, 0.00021 mol) in THF (2.0 mL) at 5° C., wasadded triethyl amine (0.036 g, 0.00035 mol) followed by the addition ofacetoxyacetyl chloride (0.05 mL). The mixture was stirred at roomtemperature for 30 min, diluted with cold water (10 mL), and extractedthe products with dichloromethane (2×10 mL). The combined organicextracts were washed with water, dried (Na₂SO₄) and concentrated todryness. The residue was dissolved in ethanol (0.5 mL), added 1N NaoH(0.5 mL) and stirred at room temperature for 1 h. The resulting solutionwas diluted with water (15 mL), and extracted with dichloromethane (2×10mL). The combined dichloromethane extracts were washed with water, dried(Na₂SO₄) and concentrated to dryness. The residue was purified by flashchromatography (1% MeOH in EtOAc) to afford the title compound (0.032 g,30%) as a white amorphous powder: ¹H NMR (CDCl₃/400 Hz) δ7.45 (m, 2H),7.18 (m, 1H), 7.05 (m, 3H), 6.23 (s, 1H), 5.24 (s, 2H), 4.56 (d, 2H,J=6.4 Hz), 4.08 (d, 2H, J=5.2 Hz), 2.79 (t, 1H), and 2.08 (s, 3H;) ¹⁹FNMR (CDCl₃/400 MHz) δ −11188 (m), and −118.62 (m); ES-HRMS m/z 511.0482(M+H C₂₂H₁₉N₂O₄F₃Br requires 511.0475).

Example 382

Ethyl2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

To solution of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.3 g, 0.00057 mol) in dimethylacetamide (3.0 mL) wasadded N-methymorpholine (0.064 g, 0.00064 mol), followed by addition ofethylchloroformate (0.06 mL) and stirred at −10° C., for 30 min. Thesolvents were distilled in vacuo and the residue was purified byreverse-phase HPLC purification using 10-90% CH₃CN/Water (30 mingradient) at a flow rate of 100 mL/min. The appropriate fractions(m/z=481 M+H) were combined and freeze-dried, and the residue waspartitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20mL). The organic phase was washed with water, dried (Na₂SO₄) andconcentrated to dryness under reduced pressure, to afford the titlecompound as a white amorphous powder (0.15 g, 55%): ¹H NMR (CD₃OD/400MHz) δ7.61 (m, 1H), 7.52 (m, 1H), 7.26 (˜t, 2H, J=8.4 Hz), 7.12 (dd, 1H)7.05 (3d, 1H, J=2.4 Hz), 6.74 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H), 4.05(q, 2H, J=7.2 Hz), 2.12 (s, 3H), and 1.21 (t, 3H, J=7.2 Hz); ES-HRMS m/z481.1118 (M+H C₂₃H₂₁N₂O₄F₃Cl requires 481.1136).

Example 383

Isobutyl2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 382. Yield 57%; ¹H NMR (CD₃OD/400 MHz) δ7.61 (m,1H), 7.51 (m, 1H), 7.24 (˜t, 2H, J=8.0 Hz), 7.18 (m, 1H), 7.06 (m, 1H),6.74 (s, 1H), 5.40 (s, 2H), 4.21 (s, 2H), 3.79 (d. 2H, J=6.8 Hz), 2.12(s, 3H), 1.85 (m, 1H), and 0.91 (d, 6H, J=6.4 Hz); ES-HRMS m/z 509.1422(M+H C₂₅H₂₅N₂O₄F₃Cl requires 509.1449)

Example 384

Cyclopropylmethyl2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

The title compound was prepared by a procedure similar to the onedescribed for EXAMPLE 382. Yield 46%; ¹H NMR (CD₃OD/400 Hz) δ7.61 (m,1H), 7.55 (m, 1H), 7.24 (˜t, 2H, J=7.6 Hz), 7.18 (m, 1H), 7.05 (m, 1H),6.73 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H), 3.83 (d, 2H, J=7.2 Hz), 2.12(s, 3H), 1.1 (br, 1H), 0.58 (˜d, 2H), and 0.22 (˜d, 2H); ES-HRMS m/z507.1316 (M+H C₂₅H₂₃N₂O₄F₃Cl requires 507.1293).

Example 385

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate Step 1

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (0.9 g, 0.007 mol) and4-amino-5-aminomethyl-2-methylpyrimidine (1.0 g, 0.007 mol) in water(10.0 ml) was heated at 100° C. for 1 h under argon atmosphere. Thereaction mixture was cooled, and filtered the yellow precipitate. It waswashed successively with cold water, ethanol, and dried in vacuo toafford the title compound (1.01 g, 51%) as a pale yellow powder: ¹H NMR(DMSO-d₆/400 MHz) δ7.62 (s, 1H), 7.04 (s, 1H), 5.83 (d, 1H, J=2.0 Hz),5.58 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H);ES-HRMS m/z 325.0304 (M+H C₁₂H₁₄N₄O₂Br requires 325.0295).

Step 2

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-hydroxy-6-methylpyridin-2(1H)-one

A mixture of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-hydroxy-6-methylpyridin-2(1H)-one(0.5 g, 0.002 mol), and NBS (0.4 g, 0.002 mol)in glacial acetic acid(5.0 ml) was stirred at room temperature for 1 h under argon atmosphere.Acetic acid was removed in vacuo, residue was triturated with EtOAccontaining 10% EtOH, and filtered. The pale yellow precipitate waswashed with EtOAc containing 10% EtOH and dried in vacuo to afford thetitle compound (0.47 g, 725) as a pale yellow powder:

¹H NMR (CD₃OD/400 MHz) δ7.62 (s, 1H), 6.09 (s, 1H), 5.15 (s, 2H), 2.42(s, 3H), and 2.33 (s, 3H); ES-HRMS m/z 247.1160 (M+H C₁₂H₁₅N₄O₂ requires247.1190).

Step 3

To suspension of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-hydroxy-6-methylpyridin-2(1H)-one(1.0 g, 0.0031 mol) and potassium carbonate (0.0 g, 0.004 mol) indimethylacetamide (10.0 mL) was added 2,4-difluorobenzyl bromide (0.62mL, 0.0048 mol) and stirred at room temperature for 2 hours.Dimethylacetamide was distilled in vacuo and the residue was purified byreverse-phase HPLC using 10-90% CH₃CN/Water (30 min gradient) at a flowrate of 100 mL/min. The appropriate fractions (m/z=566)were combined andfreeze dried to afford 0.65 g (37%) of the title compound as itstrifluoroacetate salt: ¹H NMR (CD₃OD/400 MHz) δ7.65 (s, 1H), 7.58 (m,1H), 7.05 (m, 2H), 6.61 (s, 1H), 5.31 (s, 2H), 5.18 (s, 2H), 2.51 (s.3H), and 2.46 (s, 3H); ¹H NMR (CD₃OD/400 MHz) δ −111.39 (m), and −115.98(m); ES-HRMS m/z 451.0590 (M+H C₁₉H₁₈N₄O₂BrF₂ requires 451.0576).

Example 386

1-[(4amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride Ion exchange (25 g) BioRad AG 2×8 resin (200-400 meshchloride form) was washed with 1M HCl (150 mL), and equilibrated for 2.5h. This resin was loaded onto a column, and added a solution of Example385 (3.3 g, 5.8 mmol) in water/CH₃CN (1:1). The column was eluted slowlyover 1 h, fractions were collected, and freeze dried to afford thedesired HCl salt (2.2 g, 72%) as a white solid: ¹H-NMR (CD₃OD, 400 Hz) δ7.60 (m, 2H), 7.21 (m, 2H), 6.62 (s, 1H), 5.31 (s, 2H), 5.18 (s, 2H),2.52 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 451.0544/453.0577 (M+HC₁₉H₁₇N₄O₂F₂Br requires 451.0581/453.0563).

Example 387

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate Step 1. Preparation of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-hydroxy-6-methylpyridin-2(1H)-one

¹H NMR (CD₃OD, 400 Hz) δ 7.62 (m, 1H), 6.11 (s, 1H), 5.13 (s, 2H), 2.66(s, 3H), 2.42 (s, 3H); ES-HRMS m/z 281.0793 (M+H C₁₂H₁₃N₄O₂Cl requires281.0800).

Step 2. Preparation of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate

The title compound was prepared by a procedure similar to the onedescribed for Example 385 step 2. ¹H NMR (CD₃OD, 400 Hz) δ 7.59 (m, 2H),7.03 (m, 2H), 6.63 (s, 1H), 5.31 (s, 2H), 5.17 (s, 2H), 2.48 (s, 3H),2.46 (s, 3H); ES-HRMS m/z 407.1097 (M+H C₁₉H₁₇N₄O₂ClF₂ requires407.1081).

Example 388

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride

Ion exchange (12.59) BioRad AG 2×8 resin (200-400 mesh chloride form)was washed with 1M HCl (150 mL), and equilibrated for 2.5 h. This resinwas loaded onto a column, and added a solution of EXAMPLE 387 (1.2 g,2.4 mmol) in water/CH₃CN (1:1). The column was eluted slowly over 1 h,fractions were collected, and freeze dried to afford the desired HClsalt (1.03 g, 97%) as a white solid: ¹H NMR (CD₃OD, 400 Hz) δ 7.60 (m,2H), 7.04 (m, 2H), 6.64 (s, 1H), 5.31 (s, 2H), 5.17 (s, 2H), 2.50 (s,3H), 2.47 (s, 3H); ES-HRMS m/z 407.1079 (M+H C₁₉H₁₇N₄O₂ClF₂ requires407.1081).

Example 389

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-ylmethyl)-6-methylpyridin-2(1H)-onetrifluoroacetate

To a mixture of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.55 g,0.0017 mol) and 5-(bromomethyl)-1-tetrahydro-2H pyran-2-yl-1H-indazole(0.5 g, 0.0017 mol) in THF (10.0 mL) was added NaH (0.045 g, 0.0019 mol)and heated at

60° C. for 16 h under argon atmosphere. THF was distilled under reducedpressure, and the residue was suspended in EtOAc, added acetic acid (0.5mL) and the product was purified by flash chromatography (80% EtOAc inhexane). The appropriate fractions were combined and concentrated togive an amorphous substance (0.31 g). This was stirred withtrifluoroacetic (0.5 mL) for 30 min, the solution was diluted withacetonitrile (5 mL) and the product was isolated by reverse-phase HPLCusing 10-90% CH₃CN/Water (30 min gradient) at a flow rate of 100 mL/min.The appropriate fractions (m/z=460) were combined and freeze dried toafford 0.14 g (52%) of the title compound as its trifluoroacetate salt:¹H NMR (CD₃OD/400 MHz) δ7.97 (s, 1H), 7.62 (m, 1H), 7.51 (m, 1H), 7.45(s, 1H), 7.25 (m, 1H), 7.03 (t, 2H), 6.49 (s, 1H), 5.53 (s, 2H), 5.29(s, 2H), and 2.40 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −111.69 (m),−116.09 (m); ES-HRMS m/z 460.0432 (M+H C₂₁H₁₇N₃O₂BrF₂ requires460.0467).

Example 390

N˜1˜-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)glycinamidetrifluoroacetate

To a solution of BOC-Gly-OH (0.19 g, 0.0011 mol) in DMP (2.0 mL), wasadded N-methylmorpholine (0.14 mL, 0.0011 mol), followed by the additionof isobutylchloroformate (0.15 mL, 0.0011 mol) and stirred at −10° C.for 15 min. Then added a solution of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate (0/125 g, 0.00022 mol) in DMF (2.0 mL) containingdiisopropylethylamine (0.1 g, 0.006 mL) and the resulting mixture wasstirred for 16 h, at room temperature. The solvents were distilled invacuo and the residue was purified by reverse-phase HPLC using 10-90%CH₃CN/Water (30 min gradient) at a flow rate of 100 mL/min. Theappropriate fractions (m/z 608/610) were combined and freeze dried toafford 0.025 g of white powder. This was stirred with trifluoroaceticacid (0.5 mL) for 1 h and product was isolated by reverse-phase HPLCusing 10-90% CH₃CN/Water (30 min gradient) at a flow rate of 100 mL/min.The appropriate fractions (m/z=508/510) were combined and freeze driedto afford the title compound (0.02 g) as a white powder: ¹H NMR(CD₃OD/400 MHz) δ8.18 (s, 1H), 7.61 (m, 1H), 7.02 (m, 2H), 6.59 (s, 1H),5.30 (s, 4H), 4.23 (s, 2H), 2.60 (s, 3H), and 2.47 (s, 3H); ES-HRMS m/z508.0797 (M+H C₂₁H₂₁N₅O₃BrF₂ requires 508.0790).

Example 391

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-oneStep 1

4-(Bromomethyl)-2-(methylthio)pyrimidine

To a solution of 4-methyl-2-methylthiopyrimidine (12.6 g, 0.09 mol) inacetic acid (50.0 mL) was added bromine (5.5 mL, 0.11 mol) and heated at80° C. under argon atmosphere for 2 h. Acetic acid was distilled invacuo, the residue was triturated with dichloromethane (100.0 mL) andpoured into satd. sod.bicarbonate solution (200.0 mL). Additionaldichloromethane (100.0 ml) was added and stirred for 15 min. The organicphase was washed with water (3×100 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The dark colored residue was purified by flashchromatography (EtOAc/hexane 1:4 v/v) to afford4-(bromomethyl)-2-(methylthio)pyrimidine (10.9 g, 55%) as a dark coloredliquid: ¹H NMR (CDCl₃/400 MHz) δ8.50 (d, 1H, J=4.8 Hz), 7.09 (d, 1H,J=4.8 Hz), 4.34 (s, 2H), and 2.56 (s, 3H); ESMS m/z 219 (M+H).

Step 2

To a mixture of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one 5.0 g,0.015 mol) and 4-(Bromomethyl)-2-(methylthio)pyrimidine (4.0 g, 0.018mol) in THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55°C. under argon for 16 h. The reaction mixture was concentrated underreduced pressure and the residue was partitioned between 5% citric acid(25 mL) and EtOAc (50 mL). A precipitate was formed, it was filtered,washed with water, EtOAc, and dried in vacuo to afford the titlecompound (4.2 g, 59%) as a light brown powder, ¹H NMR (CD₃OD/400 MHz)δ8.45 (d, 1H, J=5.2 Hz), 7.6 (m, 1H), 7.06 (d over m, 2H, J=5.2 Hz),6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H);ES-HRMS m/z 468.0173 (M+H C₁₉H₁₇N₃O₂BrSF₂ requires 468.0187).

Example 392

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylsulfonyl)pyrimidin-4-yl]methyl}pyridin-2(1H)-one

A suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-one0.28 g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate 90.6g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0 ml) was stirredat room temperature for 16 h. The resulting clear solution wasconcentrated under reduced pressure, and the residue was partitionedbetween dichloromethane (30 mL) and water (20 mL). The organic phase waswashed with water, dried (Na₂SO₄) and concentrated to afford the titlecompound (0.27 g, 90%) as a pale yellow substance: ¹H NMR (CD₃OD/400MHz) δ 8.91 (d, 1H, J=5.2 Hz), 7.63 (d over m, 2H, J=5.2 Hz), 7.03 (m,2H), 6.58 (s, 1H), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H), and 2.49(s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −111.58 (m), −115.98 (m); ES-HRMS m/z500.0113 (M+H C₁₉H₁₇N₃O₄BrSF₂ requires 500.0086).

Example 393

4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitriletrifluoroacetate

A mixture of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylsulfonyl)pyrimidin-4-yl]methyl}pyridin-2(1H)-one(1.0 g, 0.002 mol) and NaCN (0.15 g, 0.0031 mol) in DMF (5.0 mL) wasstirred at room temperature for 2 h under argon atmosphere. DMF wasdistilled in vacuo, the residue was triturated with acetonitrile (10 mL)and water (10 mL), and filtered the red colored precipitate. It waswashed with acetonitrile and dried to afford the title compound (0.26g). The washings and the filtrate were combined and purified byreverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) ata flow rate of 100 mL/min to give an additional 0.5 g of the titlecompound: ¹H NMR (CD₃OD/400 MHz) 8883 (d, 1H, J=5.2 Hz), 7.62 (d over m,2H, J=5.2 Hz), 7.00 (m, 2H), 6.58 (s, 1H), 5.46 (s, 2H), 5.33 (s, 2H),and 2.47 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −111.64 (m), −116.03 (m);ES-HRMS m/z 447.0278 (M+H C₁₉H₁₄N₄O₂BrF₂ requires 447.0263).

Example 394

4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate

To a solution of4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitriletrifluoroacetate (0.3 g. 0.00066 mol) in a solvent mixture of EtOAc(15.0 mL) and acetic acid (5.0 mL), was added Pd/C (10%, 0.18 g) andstirred in an atmosphere of hydrogen at 15 psi for 2 h. The catalyst wasremoved by filtration. The filtrate was concentrated to dryness and theresidue was residue was purified by reverse-phase HPLC using 10-90%acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. Theappropriate fractions (m/z=451) were combined and freeze dried to afford(0.32 g, 645) of the title compound as its trifluoroacetate salt: ¹H NMR(DMSO-d₆/400 mHz) δ8.78 (d, 1H, J=5.2 Hz), 8.28 (br, 2H), 7.62 (m, 1H),7.38 (m, 1H), 7.25 (d, 1H, J=5.2 Hz), 7.18 (m 1H), 6.62 (s, 1H), 5.32(s, 2H), 5.29 (s, 2H), 4.24 (s, 2H), and 2.46 (s, 3H); ¹⁹F NMR(DMSO-d₆/400 MHz) δ −109.59 (m), −113.67 (m); ES-HRMS m/z 451.0530 (M+HC₁₉H₁₈N₄O₂BrF₂ requires 451.0576).

Example 395

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-methoxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-onetrifluoroacetate

A solution of4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2carbonitrile trifluoroacetate (0.13 g, 0.00023 mol) in MeOH (2.0 mL) wastreated with 1N NaOH (0.5 mL). After stirring at room temperature for 3h, it was heated at 60° C. for an additional 3 h and left overnight roomtemperature. The resulting solution was diluted with acetonitrile, andpurified by reverse-phase HPLC using 10-90% acetonitrile/water gradient(30 min) at a flow rate of 100 mL/min. The appropriate fractions(m/z=452) were combined and freeze dried to afford the title compound(0.015 g) as a white powder: ¹H NMR (CD₃OD) δ8.84 (d, 1H, J=5.2 Hz) 7.62(d, 1H, J=5.2 Hz), 7.05 (m, 2H), 6.57 (s, 1H), 5.49 (s, 2H), 5.32 (s,2H), 3.96 (s, 3H), and 2.49 (s, 3H); ES-HRMS m/z 452.0440 (M+HC₁₉H₁₇N₃O₃BrF₂ requires 452.0416).

Example 396

Methyl4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carboxylatetrifluoroacetate

The title compound was obtained as a second product in the formation of3-Bromo-4-[[(2,4-difluorobenzyl)oxy]-1-(2-methoxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-onetrifluoroacetate. ¹H NMR (CD₃OD/400 MHz) δ8.46 (d, 1H, J=5.2 Hz), 7.62(m, 1H), 7.00 (m 2H), 6.93 (d, 1H, J=5.2 Hz), 6.55 (s, 1H), 5.39 (s,2H), 5.32 (s, 2H), 3.85 (s, 3H), and 2.44 (s, 3H); ES-HRMS m/z 480.0340(M+H C₂₀H₁₇N₃O₄BrF₂ requires 480.0365).

Example 397

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-hydroxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-onetrifluoroacetate

A mixture of4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitriletrifluoroacetate (0.2 g, 0.00035 mol) potassium fluoride on aluminumoxide (0.25 g) in t-butanol (5.0 mL) was refluxed for 4 h under argonatmosphere. The reaction mixture was cooled, filtered the precipitateand washed with ethanol. The combined filtrate and washings wereconcentrated to dryness and the residue was purified by reverse-phaseHPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of100 mL/min. The appropriate fractions (m/z=452) were combined and freezedried to afford the title compound (0.05 g) as a white powder:

¹H NMR (DMSO-d₆/400 Mz) δ7.85 (d, 1H J=6.4 Hz), 7.64 (m, 1H), 7.30 (m1H), 7.15 (m 1H), 6.55 (s, 1H), 6.22 (d, 1H, J=6.4 Hz), 5.28 (s, 2H),5.12 (d, 2H), and 2.29 (s, 3H); ¹⁹F-NMR (DMSO-d₆/400 MHz) δ −109.69 (m),and −113.67 (m); ES-HRMS m/z 438.0228 (M+H C₁₈H₁₅N₃O₃BrF₂ requires438.0259).

Example 398

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carboxamidetrifluoroacetate

The title compound was obtained by a procedure described for Example397. ¹H NMR (DMSO-d₆/400 MHz) δ882 (d, 1H J=5.2 Hz), 8.01 (br, 1H), 7.79(br 1H), 7.64 (m, 1H), 7.34 (m, 2H), 7.16 (m 1H), 6.62 (s, 1H), 5.36 (s,2H), 5.30 (s, 2H), and 2.38 (s, 3H); ¹⁹F NMR (DMSO-d₆/400 MHz) δ −109.64(m), and −113.66 (m) ES-HRMS m/z 465.0385 (M+H C₁₉H₁₆N₄O₃BrF₂ requires465.0368).

Example 399 Methyl(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidin-2-yl)methylcarbamate

To a solution of4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.13 g, 0.00023 mol) in dimethylacetamide (1.0 mL),was added triethylamine (0.04 mL, 0.0003 mol), followed by the additionof methylchloroformate (0.05 mL) and stirred at 0° C. for 30 min underargon atmosphere. The reaction mixture was diluted with water (10 mL)and extracted with EtOAc (2×20 mL), The combined organic extracts werewashed with water, dried (Na₂SO₄) and concentrated to dryness. Theresulting residue was purified by flash chromatography (5% MeOH inEtOAc) to afford the title compound (0.055 g, 37%) as pale yellowpowder: ¹H NMR (DMSO-d₆/400 MHz) δ8.65 (d, 1H J=5.6 Hz), 7.63 (1H), 7.5(m, 1H), 7.28 (m 1H), 7.13 (m, 2H), 6.59 (s, 1H), 5.28 (s, 4H), 5.26 (d,2H, J=6.0 Hz), and 2.46 (s, 3H); ¹⁹F NMR (DMSO-d₆/400 MHz) δ −109.64(m), and −113.71 (m); ES-HRMS m/z 509.0621 (M+H C₂₁H₂₀N₄O₄BrF₂ requires509.0630).

Example 400

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5methylpyrazin-2-yl)methyl]pyridin-2(1H)-one Step 1

4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (5.0 g, 0.04 mol) and5-aminomethyl-2-methylpyrazine (5.0 g, 0.041 mol) in water (25.0 ml) washeated at 100° C. for 1 h under argon atmosphere. The reaction mixturewas cooled, and filtered the yellow precipitate. It was washed withethanol, and dried in vacuo to afford the title compound (5.8 g, 63%) asa pale yellow powder: ¹H NMR (DMSO-d₆/400 MHz) δ10.43 (br, 1H), 8.38 (d,2H, J=5.2 Hz), 5.77 (d, 1H, J=2.0 Hz), 5.58 (d, 1H, J=2.0 Hz), 4.92 (s,2H), 2.24 (s, 3H), and 2.22 (s, 3H); ESMS m/z 232 (M+H).

Step 2

3-Bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one

The title compound was prepared by a procedure described in step 2 forExample 385.

Yield: 64%, ¹H NMR (CD₃OD/400 MHz) δ8.47 (s, 1H), 8.42 (s, 1H), 6.07 (s,1H), 5.38 (s, 2H), 2.51 (s, 3H), and 2.44 (s, 3H), ESMS m/z 310 and 312(M+H).

Step 3

To a mixture of3-Bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one(0.45 g, 0.0015 mol), and potassium carbonate (0.25 g, 0.0018 mol) indimethylacetamide (5.0 mL) was added 2,4-difluorobenzyl bromide (0.25mL. 0.0019 mol) and stirred at room temperature under argon for 1 h.Dimethylacetamide was distilled in vacuo and the residue was partitionedbetween CH₂Cl₂ (20 mL) and water (20 mL). The organic phase was washedwith water, dried (Na₂SO₄) and concentrated under reduced pressure. Theresulting material was purified by flash chromatography (EtOAc/hexane4:1 v/v) as the eluent. The appropriate fractions (m/z=451/453) werecombined and concentrated under reduced pressure to give a white (0.25g, 38%)solid. ¹H NMR (CD₃OD/400 MHz) δ8.49 (s, 1H), 8.40 (s, 1H), 7.60(m, 1H), 6.99 (m, 2H), 6.51 (s, 1H), 5.42 (s, 2H), 5.29 (s, 2H), 2.54(s, 3H), and 2.50 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −117.70 (m), and−116.09 (m); ES-HRMS m/z 436.0439 (M+H C₁₉H₁₇N₃O₂BrF₂ requires436.0467).

Example 401

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyrazin-2-ylmethyl)pyridin-2(1H)-oneStep 1

2-Chloromethylpyrazine

A mixture of 2-methylpyrazine (3.5 g, 0.037 mol), NCS (6.3 g, 0.047 mol)and benzoyl peroxide (0.05 g) was heated to reflux for 16 h under argonatmosphere. It was filtered and the filtrate was concentrated todryness. The resulting residue was purified by flash chromatographyusing 30% EtOAc in hexane to afford 2-chloromethylpyrazine as a darkcolored liquid (1.7 g, 36 5): ¹H NMR (CD₃OD/400 MHz) δ8.75 (d, 1H, J=1.2Hz), 8.58 (m, 1H), 8.56 (m, 1H), and 4.75 (s, 2H); ESMS m/z=129 (M+H).

Step 2

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.8 g,0.0055 mol) and 2-chloropyrazine (0.8 g, 0.00625) were suspended in THF(25 mL), then added NaH (0.15 g, 0.0062 mol), KI (0.1 g) and the mixturewas heated at 65° C. under argon atmosphere for 16 h. The reactionmixture was cooled, added acetic acid (0.5 mL) and concentrated todryness under reduced pressure. The residue was stirred with a mixtureof water (50 mL) and EtoAc (25 mL) and filtered the precipitate. It waswashed with water, and acetonitrile an dried in vacuo to afford 1.7 g oflight brown powder. ¹H NMR (CD₃OD/400 MHz) δ8.65 (d, 1H), δ 49 (m, 1H),8.47 gm, 1H), 7.61 (˜q, 1H), 7.02 (m, 2H), 6.52 (s, 1H), 5.47 (s, 2H),5.23 (s, 2H), and 2.53 (s, 3H);

¹⁹F NMR (CD₃OD/400 MHz) δ −111.72 (m), and −116.07 (m); ES-HRMS m/z422.0283 (M+H C₁₈H₁₅N₃O₂BrF₂ requires 422.0310).

Example 402

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-oneStep 1

Ethyl 5-methylpyrazine-2-carboxylate

A solution of 5-methylpyrazine-2-carboxylic acid (15.0 g, 0.109 mol) inethanol (70.0 mL) containing (1.5 g, 0.0079 mol) was heated to refluxfor 4 h under argon atmosphere. The dark colored solution was cooled,added sod.bicarbonate (1.0 g) and concentrated under reduced pressure.The residue was partitioned between water (50 mL) and EtOAc (100 mL).The organic layer was washed with water (2×25 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to afford ethyl5-methylpyrazine-2-carboxylate (12.05 g, 67%) as an orange coloredliquid: ¹H NMR (CD₃OD/400 MHz) δ9.1 (d. 1H, J=1.2 Hz), 8.62 (d, 1H,J=1.2 Hz), 4.45 (q, 2H, J=7.2 Hz), 2.63 (s, 3H), and 1.41 (t, 3H, J=7.2Hz); ESMS m/z 167 (M+H).

Step 2

Ethyl 5-(bromomethyl)pyrazine-2-carboxylate

A solution of ethyl 5-methylpyrazine-2-carboxylate (12.0 g, 0.072 mol)in glacial acetic acid (60 mL) containing bromine (4.0 mL) was heated at80° C. under anhydrous conditions for 45 min. After the removal ofacetic acid in vacuo, the residue was partitioned between saturated,bicarbonate (100 mL) and EtOAc (3×30 mL). The combined EtOAc extractswere washed with water (2×25 mL), dried (Na₂SO₄), and concentrated underreduced pressure. The resulting liquid was purified by flashchromatography (20% EtOAc in hexane) to affordethyl-(5bromomethylpyrazine-2-carboxylate (7.7 g, 44%) as an orangecolored liquid: ¹H NMR (CD₃OD/400 MHz) δ9.18 (d. 1H, J=1.2 Hz), 8.85 (d,1H, J=1.2 Hz), 4.71 (d, 2H), 4.47 (q, 2H, J=7.2 Hz), and 1.42 (t, 3H,J=7.2 Hz); ES-HRMS m/z 244.9942 (M+H C₈H₁N₂O₂Br requires 244.9920).

Step 3

Ethyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate

To a mixture of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (6.0 g,0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02mol) in THF (50.0 mL) was added NaH (0.5 g) and heated at 55° C. underargon atmosphere for 3 h. The reaction mixture was cooled added aceticacid (1.2 ml) and concentrated under reduced pressure. The residue wastriturated with water and filtered the solid. It was washed with water,followed by ethanol and dried in vacuo to afford the title compound (3.0g, 78%)as alight brown powder: ¹H NMR (CD₃OD/400 MHz) δ9.10 (d. 1H,J=1.2 Hz), 8.77 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s,1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J=6.8 Hz), 2.52 (s, 3H),and 1.39 (t, 3H, J=6.8 Hz); ¹⁹F NMR (CD₃OD/400 MHz) δ−111.64 (m), and−116.04 (m); ES-HRMS m/z 494.0482 (M+H C₂₁H₁₉N₃O₄BrF₂ requires494.0522).

Step 4

To a suspension of ethyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate(2.0 g, 0.004 mol) in t-butanol (15.0 mL and THF (5.0 mL) was addedNaBH₄ (0.18 g, 0.0047 mol) and the mixture was stirred at roomtemperature for 16 h under argon atmosphere. It was cooled, added MeOH(5.0 mL) and acetic acid (1.0 mL) and concentrated to dryness. Theresidue was triturated with water and filtered. It was washed withwater, dried in vacuo and purified by flash chromatography (1% MeOH inEtOAc to afford the title compound (0.75 g, 41%) as a pale yellowpowder: ¹H NMR (CD₃OD/400 MHz) δ 8.58 (d. 1H, J=1.6 Hz), 8.56 (d, 1H,J=1.6 Hz), 7.6 (m, 1H), 7.01 (m, 2H), 6.52 (s, 1H), 5.46 (s, 2H), 5.29(s, 2H), 4.71 (s, 2H), and 2.54 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ−111.70 (m), and −116.06 (m); ES-HRMS m/z 452-0394 (M+H C₁₉H₁₇N₃O₃BrF₂requires 452.0416).

Example 403

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(dimethylamino)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-onetrifluoroacetate Step 1

3-Bromo-1-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Cyanurylchloride (0.42 g, 0.0023 mol) was added to DMF (0.52 mL) andstirred at room temperature for 15 min. Then added dichloromethane (15mL) followed by the addition of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one1.0 g, 0.0022 mol) and reaction mixture was stirred at room temperatureunder argon atmosphere. After 1 h, an additional 1.0 mL of DMF was addedand the reaction was allowed to proceed for another hour, when a clearsolution was obtained. The solution was diluted with dichloromethane (20mL) and washed with water, dried (Na₂SO₄), and concentrated to drynessunder reduced pressure. The residue was triturated with EtOAc, filtered,washed with EtOAc and dried to afford 0.79 g (77%) of the title compoundas a pale yellow powder: ¹H NMR (CD₃OD/400 MHz) δ 8.66 (s, 2H), 7.73 (m,1H), 7.05 (m, 2H), 6.56 (s, 1H), 5.52 (s, 2H), 5.33 (s, 2H), 4.74 (s,2H), and 2.57 (s, 3H); ES-HRMS m/z 470.0051 (M+H C₁₉H₁₆N₃O₂BrClF₂requires 470.0077).

Step 2

A suspension of3-Bromo-1-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(0.25 g, 0.00053 mol) in THF (1.0 mL) was treated with N, N,-dimethylamine (1.0 mL of 2M soln in THF) and stirred at room temperature for 16h. The reaction mixture was concentrated and the title compound wasisolated by reverse-phase HPLC using 10-90% acetonitrile/water gradient(30 min) at a flow rate of 100 mL/min. The appropriate fractions(m/z=479) were combined and freeze dried to afford the title compound(0.27 g, 87%) as a white powder: ¹H NMR (CD₃OD/400 MHz) δ8.78 (d. 1H, JHz), 8.56 (d, 1H, J=1.2 Hz), 7.61 (m 1H), 7.01 (m, 2H), 6.55 (s, 1H),5.49 (s, 2H), 5.30 (s, 2H), 4.52 (s, 2H), 2.94 (s, 6H) and 2.57 (s, 3H);¹⁹F NMR (CD₃OD)=δ−111.56 (m) and −116.02 (m); ES-HRMS m/z 479.0885 (M+HC₂₁H₂₂N₄O₂BrF₂ requires 479.0889).

Example 404

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(5-{[(2-hydroxyethyl)(methyl)amino]-methyl}pyrazin-2-yl)methyl]-6-methylpyridin-2(1H)-onetrifluoroacetate

The title compound was prepared in a similar manner as described forExample 403, substituting N-methylaminoethanol for N,N-dimethylamine.Yield=78%,

¹H NMR (CD₃OD/400 MHz) δ 8.78 (d. 1H, J Hz), 8.59 (d. 1H, J=1.2 Hz), 7.6(m, 1H), 7.01 (m, 2H), 6.55 (s, 1H), 5.49 (s, 2H), 5.30 (s, 2H), 3.89(˜t, 2H), 2.97 (s, 3H), and 2.57 (s, 3H); ¹⁹F NMR (CD₃OD/400MHz)=δ−111.56 (m) and −116.04 (m); ES-HRMS m/z 509.0964 (M+HC₂₂H₂₄N₄O₃BrF₂ requires 509.0994).

Example 405

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-onetrifluoroacetate Step 1

5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid

A suspension of ethyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine2-carboxylate (0.18 g, 0.002 mol) and 1N NaOH (0.6 mL in 1:1 v/vEtOH/Water) was stirred at room temperature for 1.5 h. The reactionmixture was acidified with 5% citric acid and filtered the precipitate.It was washed with water, followed by ethanol and dried in vacuo toafford the title compound (0.14 g, 77%) as a light brown powder: ¹H NMR(CD₃OD/400 MHz)=δ 9.03 (s. 1H), 8.60 (s, 1H), 7.61 (m. 1H), 7.00 (m,2H), 6.52 (s, 1H), 5.51 (s, 2H), 5.30 (s. 2H), and 2.52 (s, 3H); ¹⁹F NMR(CD₃OD/400 MHz)=δ−8-111.75 (m) and −116.06 (m); ES-HRMS m/z 466.0209(M+H C₁₉H₁₅N₄O₃BrF₂ requires 466.0209).

Step 2

To a solution of5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid (0.28 g, 0.0006 mol) in DMF (3.0 mL), at −15° C., was addedisobutylchloroformate (0.082 g, 0.0006 mol), followed by the addition ofN-methylmorpholine (0.06 g, 0.00063 mol) and stirred under argon for 15min. N-methylpiperazine (0.072 g, 0.00072 mol) in DMF (2.0 mL) was thenadded to the reaction and the mixture was stirred at room temperaturefor 3 h. After the removal of the solvents in vacuo, the residue waspurified by reverse-phase HPLC using 10-90% acetonitrile/water gradient(30 min) at a flow rate of 100 mL/min. The appropriate fractions(m/z=548) were combined and freeze dried to afford the title compound(0.32 g, 80%) as a white powder: ¹H NMR (CD₃OD/400 MHz) δ8.89 (d. 1H,J=1.6 Hz), 8.73 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 7.01 (m, 2H), 6.56 (s,1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.9 (s, 3H), and 2.57 (s, 3H); ¹⁹F NMR(CD₃OD/400 MHz)=δ−109.36 (m) and −114.91 (m); ES-HRMS m/z 548.1090 (M+HC₂₄H₂₅N₅O₃BrF₂ requires 548.1103).

Example 406

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one

A solution of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(4-methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(1H)-onetrifluoroacetate (0.17 g, 0.00026 mol) in 0.1N NaOH (25 mL) was stirredat room temperature for 15 min. and extracted the product in ethylacetate (2×20 mL). The combined organic extracts were washed with water(2×20 mL), dried (Na₂SO₄) and concentrated to dryness. The residue wasdried in vacuo to afford the title product (0.09 g, 64%) as a whitepowder: ¹H NMR (CD₃OD/400 MHz) δ8.69 (d. 1H, J=1.2 Hz), 8.67 (d, 1H,J=1.2 Hz), 7.60 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 5.50 (s, 2H), 5.30(s, 2H), 3.78 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 2.526 (s, 3H),2.53 (t, 2H, J=4.8 Hz), 2.44 (t, 2H, J=4.8 Hz), and 2.31 (s, 3H); ¹⁹FNMR (CD₃OD/400 MHz)=δ −111.65 (m) and −116.06 (m); ES-HRMS m/z 548.1123(M+H C₂₄H₂₅N₅O₃BrF₂ requires 548.1103).

Example 407

5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide

The title compound was prepared in a similar manner as described forExample 405, substituting N-methylpiperazine by N-methylethanolamine.Yield=60%,

¹H NMR (CD₃OD/400 MHz) δ8.69 (d. 1H, J=1.2 Hz), 8.64 (d. 1H, J=1.2 Hz),7.61 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 5.49 (s. 2H), 5.30 (s, 2H),3.81 (˜t, 1H), 3.66 (m, 2H), 3.56 (t, 1H, J=5.2 Hz), 3.12 (d, 3H J=7.6Hz), 2.56 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ−109.64 (m) and −113.66 (m);ES-HRMS m/z 523.0743 (M+H C₂₂H₂₂N₄O₄BrF₂ requires 523.0797).

Example 408

5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2,3-dihydroxypropyl)pyrazine-2-carboxamide

The title compound was prepared in a similar manner as described forEXAMPLE 405, substituting N-methylpiperazine by 3-amino-1,2-propanediol.Yield=56%; ¹H NMR (CD₃OD/400 MHz) δ9.09 (d. 1H, J=1.2 Hz), 8.70 (d. 1H,J=1.2 Hz), 7.60 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 5.53 (s. 2H), 5.30(s, 2H), 3.80 (m, 1H), 3.61 (dd, 1H), 5.53 (d, 2H), J=5.2 Hz), 3.42 (dd,1H), and 2.55 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) δ −109.65 (m), and−113.67 (m); ES-HRMS m/z 539.0703 (M+H C₂₂H₂₂N₄O₄BrF₂ requires539.0736).

Example 409

5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)pyrazine-2-carboxamide

The title compound was prepared in a similar manner as described forEXAMPLE 405, substituting N-methylpiperazine by 2-aminoethanol.Yield=46%; ¹H NMR (CD₃OD/400 Hz) δ 9.08 (d. 1H, J=1.2 Hz), 8.70 (d, 1H,J=1.2 Hz), 7.601 (m, 1H), 7.01 (m, 2H), 6.54 (s, 1H), 5.53 (s, 2H), 5.30(s, 2H), 3.69 (t, 2H, J=6.0 Hz), 3.53 (t, 2H, J=6.0 Hz), 2.55 (s, 3H););¹⁹F NMR (CD₃OD/400 Hz) δ−1111.67 (m) and −116.07 (m); ES-HRMS m/z509.0616 (M+H C₂₁H₂₀N₄O₄BrF₂ requires 509.0630).

Example 410

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(methoxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one

To a solution of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one(0.35 g, 0.00078 mol) in DMF at 0° C., was added NaH (0.022 g, 0.00092mol) and stirred for 10 min. Iodomethane (0.05 mL) was added to thereaction and the mixture was stirred at 10° C. for 3 h. DMF wasdistilled in vacuo and the residue was partitioned between 5% citricacid and EtOAc (15.0 mL). The organic phase was washed with water, dried(Na₂SO₄) and concentrated to dryness. The residue was purified by flashchromatography (EtOAc), and the appropriate fractions were combined andconcentrated to a pale yellow powder.

¹H NMR (CD₃OD/400 MHz) δ 8.59 (s), 8.55 (s, 1H), 7.60 (m, 1H), 6.99 (m,2H), 6.52 (s, 1H), 5.47 (s, 2H), 5.30 (s, 2H), 4.57 (s, 2H), 3.44 (s,2H), and 2.54 (s, 3H); ¹⁹F NMR (CD₃OD/400 Hz) δ−111.69 (m) and −116.09(m); ES-HRMS m/z 466.0577 (M+H C₂₁H₁₉N₃O₃BrF₂ requires 466.0572).

Example 411

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(2-methoxyethoxy)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one

To a solution of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one(0.25 g, 0.00055 mol) in dimethyl acetamide at 0° C., was added NaH(0.016 g, 0.00067 mol) and stirred for 15 min. 2-Methoxyethyl bromide(0.09 g, 0.00-65 mol) was then added, and the mixture was stirred atroom temperature for 6 h. Dimethylacetamide was distilled in vacuo andthe product was purified by reverse-phase HPLC using 10-90%acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. Theappropriate fractions (m/z=510) were combined and freeze dried to affordthe title compound (0.32 g, 80%) as a white powder:

¹H NMR (CD₃OD/400 Hz) δ8.59 (s, 1H), 8.58 (s, 1H), 7.60 (m, 1H), 7.02(m, 2H), 6.52 (s, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.67 (s, 2H), 3.71(˜t, 2H,), 3.57 (˜t, 2H), 3.34 (s, 3H), and 2.54 (s, 3H); ES-HRMS m/z510.0852 (M+H C₂₀H₁₈N₄O₄BrF₂ requires 510.0835).

Example 412

(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methylcarbamate

To a suspension of3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one(0.21 g, 0.00055 mol) in THF (5.0 mL) and DMF (2.0 mL), was added4-nitrophenylchloroformate (0.1 g, 0.0005 mol) and cooled to 0° C.Triethylamine (0.052 g, 0.0005 mol) was then added, stirred at roomtemperature for 1 h, and at 65° C. for an additional 1 h. It was cooledin an ice bath and added 2M ammonia in propanol (1.0 mL) and stirred atroom temperature for 2 h. After the removal of the solvents underreduced pressure, the residue was partitioned between 5% sod.bicarbonate, and EtOAc (25 mL). The organic phase was washed with 5%sod. bicarbonate, (3×25 mL), water (3×25 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting substance waspurified by isolated by reverse-phase HPLC using 10-90% CH₃CN/Water (30min gradient) at a flow rate of 100 mL/min. The appropriate fractions(m/z=495 M+H) were combined and freeze-dried, and the residue waspartitioned between 5% sod. bicarbonate (20 mL) and EtOAc (25 mL). Theorganic phase was washed with water, dried (Na₂SO₄) and concentrated todryness under reduced pressure, to afford the title compound as a whitepowder (0.065 g):

¹H NMR (CD₃OD/400 MHz) δ8.61 (br s, 1H), 8.54 (br s, 1H), 7.60 (m 1H),7.02 (m, 2H), 6.52 (5, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 5.15 (s, 2H),and 2.54 (s, 3H): ¹⁹F NMR (CD₃OD) δ −111.70 (m), and −116.09 (m);ES-HRMS m/z 495.0449 (M+H C₂₀H₁₈N₄O₄BrF₂ requires 495.0474).

Example 413

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamateStep 1. Preparation of 1-benzyl-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

To a chilled solution of 1-benzyl-4-hydroxypyridin-2(1H)-one (0.375 g,1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine(0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride(0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogenatmosphere at 0° C. for 30 minutes then at room temperature for 1 hour.The reaction was monitored by TLC (5% methanol in dichloromethane). Thesolvent was removed under reduced pressure and the residue was washedwith 10% citric acid and extracted with ethyl acetate. The organicextracts were combined, washed with water and dried over anhydrousNa₂SO₄. The solvent was removed under reduced pressure to afford ayellow syrup. The residue was purified by flash chromatography (silicagel) using 5% MeOH in CH₂Cl₂ to give the desired product (0.3829, 61%)as a white semisolid. ¹H-NMR (d₆-DMSO, 400 MHz) δ7.8 (d, 1H, J=7.2 Hz),7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s, 2H), 3.29 (s, 3H); ES-HRMS m/z335.1396 (M+H calculated for C₂₀H₁₉N₂O₃ requires 335.1418).

Step 2. Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate

To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-ylmethyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH₂Cl₂ (7 mL)was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction wasstirred overnight at room temperature under nitrogen atmosphere. Thereaction mixture was purified by flash chromatography (silica gel) usingethyl acetate/hexane (1:1 v/v). The appropriate fractions were collectedaccording to ES MS (M+H 413) and concentrated. The dried product showedabout 14% of di-bromonated product by analytical HPLC. The compoundswere separated by reverse phase HPLC using a 10-90% acetonitrile inwater (30 minute gradient) at a 100 mL/min flow rate to afford (afterlyophilization) the salt of the desired compound. The salt was dilutedin ethyl acetate and washed with NaHCO₃. The organic extracts were driedover anhydrous Na₂SO₄ and concentrated to afford the desired compound(0.271 g, 58%) as a beige solid. ¹H-NMR (d₆-DMSO, 400 MHz) δ7.94 (d, 1H,J=7.2 Hz), 7.29 (m, 10H), 6.48 (s, 1H), 5.12 (s, 2H), 3.33 (s, 3H);ES-HRMS m/z 413.0495 (M+H calculated for C₂₀H₁₈O₃Br requires 413.0496).

Example 414

4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one Step 1.Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one

A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g,15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS,3.86 g, 17.1 mmol) was heated at 65° C. under nitrogen for 4 hours. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by flash chromatography (silica gel) using ethylacetate/hexane (1:1 v:v). The appropriate fractions were collectedaccording to ES MS (M+H 436) and washed with Na₂SO₃ to remove the colorimpurities. The fractions were concentrated under reduced pressure anddried in vacuo to afford the desired product (6.15 g, 90%) as a lightyellow solid. ¹H-NMR (CD₃OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.47 (d,2H, J=7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.29(s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated forC₁₉H₁₆NO₂FI requires 436.0196).

Step 2. Preparation of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one

Degassed a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (2.01 g, 4.62mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere.Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. Thereaction mixture was chilled in an ice bath for 15 minutes before addingbistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprousiodide (0.2 g). The reaction was stirred at room temperature for 30minutes before heating at 60° C. under an atmosphere of argon for 2hours. The reaction mixture was filtered through a bed of celite and thefiltrate was concentrated under reduced pressure. The dark brown residuewas diluted with CH₂Cl₂ (100 mL) and washed with water. The organicextracts were combined, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The dark brown residue was purified by flashchromatography using 30% ethyl acetate in hexane. The appropriatefractions were combined and concentrated under reduced pressure toafford the desired product (1.34 g, 72%) as a light yellow solid. ¹H-NMR(CD₃OD, 400 MHz) δ7.74 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.6 Hz), 7.35(m, 4H), 7.09 (m, 3H), 6.46 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.13 (s,2H), 0.18 (s, 9H); ES-HRMS m/z 406.1638 (M+H calculated for C₂₄H₂₅NO₂FSirequires 406.1610).

Step 3. Preparation of4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one(1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C. was addedtetrabutylammoniun fluoride (0.611 g, 1.93 mmol). The reaction wasstirred at 0° C. for 15 minutes then for 1 hour at room temperature. Thereaction was concentrated under reduced pressure and the residue wasdiluted with ethyl acetate and washed with water. The organic extractswere combined, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel) using ethyl acetate in hexane (1:1 v/v). The appropriatefractions were combined and concentrated under reduced pressure toafford the desired product (0.779 g, 72%) as a gold solid. ¹H-NMR(CD₃OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.43 (d, 2H, J=7.2 Hz), 7.35(m, 4H), 7.09 (m, 3H), 6.45 (d, 1H, J=7.6 Hz), 5.27 (s, 2H), 5.13 (s,2H), 3.78 (s, 1H); ES-HRMS m/z 334.1243 (M+H calculated for C₂₁H₁₇NO₂Frequires 334.1234).

Example 415

4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one Step 1.Preparation of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one

In a Fischer-Porter bottle, added a solution of4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.5 g, 14.56 mmol) inabsolute ethanol (20 mL). Flushed the solution with nitrogen then addedpalladium catalyst (1.05 g, 10% Pd/C). Sealed bottle and evacuatedsystem. The system was purged with hydrogen gas (2×15 psi) to check forleaks. The reaction was charged with hydrogen (35 psi) and stirred atroom temperature for 45 minutes. The system was evacuated and flushedwith nitrogen. The reaction was filtered and the catalyst was carefullywashed with fresh ethanol. The filtrate was concentrated under reducedpressure ¹H-NMR (CD₃OD, 400 MHz) δ7.54 (d, 1H, J=7.6 Hz), 7.32 (m, 1H),7.06 (d, 1H, J=7.6 Hz), 6.99 (m, 2H), 6.05 (dd, 1H, J=2.4 Hz, 2.8 Hz),5.83 (d, 1H, J=2.4 Hz), 5.09 (s, 2H); ES-HRMS m/z 220.0774 (M+Hcalculated for C₁₂H₁₁NO₂F requires 220.0787).

Step 2. Preparation of 4-(benzylamino)-1-(3fluorobenzyl)pyridin-2(1H)-one

A mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.005 g, 4.5mmol) in benzylamine (15 mL) was heated at reflux (185° C.) undernitrogen atmosphere for 24 hours. The reaction was monitored by ES-MS(MH⁺ 309). The solvent was removed by vacuum distillation to give ayellow residue. ¹H-NMR (CD₃OD, 400 MHz) δ7.31 (m, 7H), 7.03 (m, 3H),5.98 (d, 1H, J=7.2 Hz), 5.45 (s, 1H), 5.00 (s, 2H), 4.30 (s, 2H);ES-HRMS m/z 309.1403 (M+H calculated for C₁₉H₁₈N₂OF requires 309.1375).

Step 3. Preparation of4-(benzylamino)-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one

To a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one(0.50 g, 1.62 mmol) in anhydrous CH₂Cl₂ (10 mL) was addedN-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred atroom temperature under a nitrogen atmosphere for 3 hours. The reactionmixture was purified by flash chromatography (silica gel) using ethylacetate in hexane (1:1 v/v). The appropriate fractions were combined andconcentrated. ¹H-NMR (CD₃OD, 400 MHz) 87.41 (d, 1H, J=7.6 Hz), 7.31 (m,6H), 7.04 (m, 3H), 5.99 (d, 1H, J=7.6 Hz), 5.08 (s, 2H), 4.53 (s, 2H);ES-HRMS m/z 387.0508 (M+H calculated for C₁₉H₁₇N₂OBrF requires387.0504).

Example 416

4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one Step 1.Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one

A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g,15.6 mmol) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) in anhydrousacetonitrile (55 mL) was heated at 65° C. for 4 hours under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureand the residue was purified by flash chromatography (ethylacetate/hexane 1:1 v/v). The appropriate fractions were collectedaccording to ES MS (M+H 436) and washed with Na₂SO₃ to remove the colorimpurities. The fractions were concentrated under reduced pressure anddried in vacuo to afford the desired product (6.15 g, 90%) as a lightyellow solid. ¹H-NMR (CD₃OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.36 (m,6H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.28 (s, 2H), 5.19 (s, 2H);ES-HRMS m/z 436.0196 (M+H calculated for C₁₉H₁₆NO₂FI requires 436.0210).

Step 2. Preparation of4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one

To a degassed solution of4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (1.03 g, 2.36mmol) in anhydrous DMF (15 mL) under argon atmosphere was addedtriethylamine (1.11 g, 11 mmol). The reaction mixture was chilled in anice bath for 15 minutes before adding tetramethyl tin (2.10 g, 11.75mmol) followed by bistriphenylphosphine-palladium chloride (0.166 g,0.24 mmol). The reaction was stirred at room temperature for 30 minutesbefore heating at 95° C. under an atmosphere of argon for 3 hours. Thereaction mixture was filtered through a bed of celite and the filtratewas concentrated under reduced pressure. The dark brown residue wasdiluted with ethyl acetate (100 mL) and washed with water. The organicextracts were combined, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The dark brown residue was purified by flashchromatography (30% ethyl acetate in hexane). The appropriate fractionswere combined and concentrated under reduced pressure to afford thedesired product (0.1758 g, 22%) as a light yellow solid. The product wasfurther purified by reverse phase HPLC using a 10-90% acetonitrile/water(30 minute gradient) at a 100 mL/min flow rate, to afford a cleanerproduct as a light yellow solid (0.0975 g, 8%). ¹H-NMR (CD₃OD, 400 MHz)δ7.58 (d, 1H, J=7.6 Hz)), 7.35 (m, 6H), 6.98 (m, 3H), 6.46 (d, 1H, J=7.6Hz), 5.19 (s, 2H), 5.15 (s, 2H), 2.0 (s, 3H); ES-HRMS m/z 324.1366 (M+Hcalculated for C₂₀H₁₉NO₂F requires 324.1394).

Example 417

1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one Step1: Preparation of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one

To a mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.1 g, 5mmol) in acetonitrile (15 mL) was added N-iodosuccinimide (1.1 g, 5.5mmol) along with a ca. amount of dichloroacetic acid (0.1 mL). Thereaction mixture stirred at room temperature for 1 hour under nitrogen.The mixture was chilled in an ice bath and filtered cold with freshMeCl₂. The beige solid was dried to afford the desired iodinatedintermediate (1.21 g, 69%). ES-LRMS m/z 346.

Step 2: Preparation of1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one

To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one(0.5 g, 1.44 mmol) in DMF (5 mL) was added K₂CO₃ (0.199 g, 1.44 mmol)followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51mmol). The reaction mixture stirred at room temperature for 30 minutes.The mixture was diluted with ethyl acetate (50 mL) and washed withwater. The organic extracts were dried over anhydrous Na₂SO₄ andconcentrated to dryness. ¹H-NMR (CD30), 400 MHz) δ7.75 (d, 1H, J=7.6Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J=7.6 Hz),5.26 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 454.0098 (M+H calculated forC₁₉H₁₅NO₂F₂I requires 454.0110).

Example 418

1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-methylpyridin-2(1H)-one

To a degassed solution of 1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3iodopyridin-2(1H)-one (0.804 g, 1.7 mmol) in DMF (10 mL) and LiCl (0.25g, 5.9 mmol) was added tetramethyltin (0.49 mL, 3.54 mmol) followed bybistriphenylphosphine-palladium chloride catalyst (0.124 g, 0.177 mmol).The reaction mixture was heated in an oil bath (85°-90° C.) undernitrogen for 3 hours. The solvent was concentrated and the residue wasdiluted with ethyl acetate and washed with water. The organic extractswere dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by flash column chromatography (20% ethyl acetatein hexane). The appropriate fractions were concentrated. ¹H-NMR (CD₃OD,400 MHz) δ 7.59 (d, 1H, J=7.6 Hz), 7.46 (m, 2H), 7.34 (m, 1H), 7.10 (m,4H), 6.46 (d, 1H, J=7.6 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 1.99 (s, 3H);ES-HRMS m/z 342.1314 (M+H calculated for C₂₀H₁₈NO₂F₂ requires 342.1300).

Example 419

1-benzyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

To a degassed cold solution of DMF (10 mL) and PPh₃ (resin, 0.93 g, 2.75mmol) was added DEAD (0.44 mL, 2.75 mmol). The reaction mixture stirredat −10° C. for 20 minutes under nitrogen. A solution of1-benzyl-3-bromo-4-hydroxy-6-methylpyridin-2(1H)-one (0.62 g, 2.1 mmol)and 2,4-difluorobenzylalcohol (0.283 mL, 2.5 mmol) in DMF (10 mL) wasadded to the resin suspension. The reaction mixture stirred at −10° C.for 30 minutes and then allowed to stir at room temperature for 1 hour.The resin was filtered and rinsed with fresh MeOH and the filtrate wasconcentrated. The residue was dissolved in ethyl acetate and purified byflash column chromatography (ethyl acetate/hexane 1:1 v/v). Theappropriate fractions were concentrated. ¹H-NMR (CD₃OD, 400 MHz) δ 7.62(m, 1H), 7.31 (m, 3H), 7.1 (d, 2H, J=7.2 Hz), 7.02 (t, 2H, J=8.6 Hz),6.48 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 2.34 (s, 3H); ES-HRMS m/z420.0399/422.0380 (M+H calculated for C₂₀H₁₇NO₂F₂Br requires420.0405/422.0387).

Example 420

N-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-4-fluorobenzamideStep 1. Preparation of 4-amino-1-(3-fluorobenzyl)pyridin-2(1H)-one

In a Fischer-Porter bottle, added a solution of4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one (2.5 g, 8.11 mmol)in glacial acetic acid (20 mL). After the solution was flushed withnitrogen, catalyst was added (10% Pd/C, 2.0 g). The vessel was sealed,evacuated, and purged with hydrogen gas. The system was charged withhydrogen gas (50 psi) and the mixture stirred at room temperature for 4hours. The system was evacuated and flushed with nitrogen. The reactionmixture was filtered through a bed of celite and washed with freshethanol. The filtrate was concentrated under reduced pressure and theresidue was purified by flash column chromatography (hexane/ethylacetate 3:4 v/v). The filtrate was concentrated. ¹H-NMR (CD₃OD, 400 MHz)δ 7.32 (q, 1H), 7.02 (m, 3H), 5.93 (dd, 1H, J=2.4 Hz, 2.8 Hz), 5.58 (d,1H, J=2.4 Hz); ES-HRMS m/z 219.0966 (M+H calculated for C₁₂H₁₂N₂OFrequires 219.0928).

Step 2. Preparation of4-fluoro-N-[1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]benzamide

To a solution of 4-amino-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.263 g,1.2 mmol) in acetonitrile (7 mL) was added a DMAP (ca.), triethylamine(0.25 mL, 1.8 mmol) and 4-fluorobenzoyl chloride (0.213 mL, 1.8 mmol).The reaction mixture stirred at 0° C. for 25 minutes and then filtered.The solid was washed with 10% citric acid and water to afford thedesired compound (0.326 g, 79%) after drying. ¹H-NMR (d₆DMSO, 400 MHz) δ7.98 (m, 2H), 7.71 (d, 1H, J=7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98(d, 1H, J=2.4 Hz), 6.61 (dd, 1H, J=2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMSm/z 341.1.

Step 3. Preparation ofN-[3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]-4-fluorobenzamide

To a mixture of4-fluoro-N-[1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]benzamide(0.305 g, 0.89 mmol) in acetonitrile (7 mL) was added NBS (0.159 g, 0.89mmol). The reaction mixture stirred at room temperature for 1.5 hours.The filtrate was removed under reduced pressure and the residue waspurified by flash column chromatography (ethyl acetate/hexane 1:1 v/v).The fractions were concentrated. ¹H-NMR (CD₃OD, 400 MHz) δ 8.03 (m, 2H),7.79 (d, 1H, J=7.6 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.28 (m, 3H), 7.12 (m,3H), 5.23 (s, 2H); ES-HRMS m/z 419.0202/421.0191 (M+H calculated forC₁₉H₁₄N₂O₂F₂Br requires 419.0201/421.0183).

Example 421

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-oneStep 1. Preparation of3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

To a mixture of1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.30 g, 1.26mmol) in dichloromethane (5 mL) was added NCS (2.52 g, 1.90 mmol). Thereaction mixture stirred at room temperature under nitrogen for 4.5hours. The suspension was cooled in ice bath, filtered, and the solidwas rinsed with fresh dichloromethane to afford the desired product(0.271 g, 79%) as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ 7.58 (m, 1H),7.22 (m, 2H), 6.20 (s 1H), 2.00 (s, 3H); ES-HRMS m/z 272.0287 (M+Hcalculated for C₁₂H₉NO₂F₂Cl requires 272.0290).

Step 2. Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one

To a solution of3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one(0.27 g, 1.00 mmol) in DMA (5 mL) was added K₂CO₃ followed by theaddition of 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol). The reactionmixture stirred at room temperature for 2 hours and then was diluted inwater. The reaction mixture was extracted with ethyl acetate, theorganic extracts were dried over Na₂SO₄ and the filtrate wasconcentrated. The resulting residue was purified by flash columnchromatography (ethyl acetate/hexane 3:4 v/v) to afford the desiredproduct. ¹H-NMR (CD₃OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m,2H), 6.71 (s, 1H), 5.36 (s, 2H), 2.11 (s, 3H); ES-HRMS m/z 398.0551 (M+Hcalculated for C₁₉H₁₃NO₂F₄Cl requires 398.0571).

Example 422

3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-oneStep 1: Preparation of1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methylpyrone (5.0 g, 0.04 mol) and4-fluorobenzylamine (10.0 g. 0.08 mol) in n-butanol (25.0 mL) was heatedto reflux for 24 hours under argon atmosphere. The resulting solutionwas concentrated to dryness under reduced pressure. The residue wastriturated with ethyl acetate and filtered. It was thoroughly washedwith ethyl acetate and dried to afford the title compound as a paleyellow powder (4.1 g. 30%). ¹H-NMR (CD₃OD, 400 MHz) δ 7.33 (q, 2H), 7.04(m, 5H), 5.85 (d, 1H, J=2.0 Hz), 5.44 (d, 2H, J=2.4 Hz), 5.20 (s, 1H),4.29 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z 341.1488 (M+H calculated forC₂₀H₁₉N₂OF₂ requires 341.1460).

Step 2: Preparation of3-bromo-1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one

To a solution of1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one(0.2857 g, 0.84 mmol) in MeCl₂ was added NBS (0.156 g, 0.88 mmol). Thereaction stirred at room temperature under nitrogen for 45 minutes. Thereaction mixture was diluted with MeCl₂ and washed with NaHCO₃. Theorganic extracts were washed with water, dried over Na₂SO₄, andconcentrated to afford the desired product (0.3242 g, 92%) as a yellowsolid. ¹H-NMR (CD₃OD, 400 MHz) δ 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s,1H), 5.28 (s, 2H), 4.50 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z419.0549/421.0537 (M+H calculated for C₂₀H₁₈N₂OBrF₂ requires419.0565/421.0547).

Example 423

3-bromo-1-(cyclopropylmethyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

To a mixture of3-bromo-1-(cyclopropylmethyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.276g, 1.07 mmol) and K₂CO₃ (0.148 g, 1.07 mmol) in DMA (4 mL) was added2,4-difluorobenzyl bromide (0.14 ml, 1.07 mmol). The mixture stirred atroom temperature for 1.5 hours. The reaction mixture was diluted inwater and extracted with ethyl acetate. The organic extracts were driedover Na₂SO₄ and concentrated. The residue was purified by flash columnchromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractionswere combined, and concentrated. ¹H-NMR (CD₃OD, 400 MHz) δ 7.60 (q, 1H),7.04 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.06 (s, 1H), 4.04 (s, 1H),2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m/z 384.0392 (M+Hcalculated for C₁₇H₁₇N₂OBrF₂ requires 384.0405).

Example 424

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin 4ylmethyl)pyridin-2(1H)-one Step 1. Preparation of3-bromo-4-hydroxy-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one

Commercially available 4 hydroxy-6-methyl pyrone (10 g, 79.3 mmol) wascondensed with commercially available 4-(aminomethyl)pyridine (8 mL,79.3 mmol) in water (50 mL). The mixture was heated in an oil bath atreflux for 1 hour under nitrogen. The solvent was evaporated. MS and¹H-NMR were consistent with the desired desbrominated structure. ¹H-NMR(CD₃OD, 400 MHz) δ 8.45 (dd, 2H, J=1.6 Hz, 1.6 Hz), 7.15 (d, 2H, J=6.0Hz), 6.00 (d, 1H, J=2.0 Hz), 5.80 (d, 1H, J=2.4 Hz), 5.34 (s, 2H), 2.23(s, 3H); ES-LRMS (M+H) m/z 217.

To a suspension of the above compound (0.801 g, 3.7 mmol) in MeCl₂ (10mL) was added NBS (0.725 g, 4.07 mmol). The reaction mixture stirred atroom temperature for 30 minutes under nitrogen. The suspension waschilled in an ice bath and filtered. The solid was washed with freshMeCl₂ and dried to afford a beige solid (0.9663 g, 88%) after drying.¹H-NMR (CD₃OD, 400 MHz) δ8.47 (d, 2H, J=5.2 Hz), 7.16 (d, 2H, J=6.0 Hz),6.09 (s, 1H), 5.40 (s, 2H), 2.24 (s, 3H); ES-LRMS (M+H) m/z 295/297.

Step 2. Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(H)-one

To a cold solution of 2,4-difluorobenzylalcohol (0.569 mL, 5.1 mmol) inTHF (5 mL) was added PPh₃ (resin, 2.55 g, 7.65 mmol) followed by theaddition of DIAD (1.48 mL, 7.65 mmol). The reaction mixture stirred at−10° C. for 15 minutes under nitrogen. A solution of3-bromo-4-hydroxy-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one (1.0g, 3.4 mmol), in DMF (10 mL) was added to the resin suspension. Thereaction mixture stirred at 0° C. for 1.5 hours and then allowed to stirat room temperature overnight. The resin was filtered and rinsed withfresh MeOH and the filtrate was concentrated. The residue was dissolvedin ethyl acetate and purified by flash column chromatography (ethylacetate). The appropriate fractions were concentrated. ¹H-NMR (CD₃OD,400 MHz) δ 8.47 (d, 2H, J=5.6 Hz), 7.63 (q, 1H), 7.15 (d, 1H, J=5.6 Hz),7.05 (m, 2H), 6.55 (s, 1H), 5.45 (s, 2H), 5.31 (s, 2H), 2.35 (s, 3H);ES-HRMS m/z 421.0366/423.0355 (M+H calculated for C₁₉H₁₆N₂O₂F₂Brrequires 421.0358/423.0339).

Example 428

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-oneStep 1. Preparation of3-bromo-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

Commercially available 4-hydroxy-6-methyl pyrone (15 g, 119.0 mmol) wascondensed with commercially available 3-(aminomethyl)pyridine (12.10 mL,119.0 mmol) in water (75 mL). The mixture was heated in an oil bath atreflux for 1 hour under nitrogen. The solvent was evaporated. ¹H-NMR(CD₃OD, 400 MHz) δ 8.43 (d, 1H, J=4.8 Hz), 8.38 (s, 1H), 7.60 (d, 1H,J=8.0 Hz), 7.39 (dd, 1H, J=4.8 Hz, 4.8 Hz), 5.97 (d, 1H, J=2.0 Hz), 5.79(d, 1H, J=2.4 Hz), 5.33 (s, 2H), 2.28 (s, 3H); ES-LRMS (M+H) m/z 217.

To a suspension of the above compound (5.01 g, 23.1 mmol) in MeCl₂ (50mL) was added NBS (4.53 g, 25.4 mmol). The reaction mixture stirred atroom temperature for 30 minutes under nitrogen. The suspension waschilled in an ice bath and filtered. The solid was washed with freshMeCl₂ and dried to afford a beige solid (7.89 g, 114%) after drying.¹H-NMR (CD₃OD, 400 MHz) δ 8.44 (d, 1H, J=4.4 Hz), 8.39 (s, 1H), 7.62 (d,1H, J=7.6 Hz), 7.39 (dd, 1H, J=5.2 Hz, 4.4 Hz), 6.07 (s, 1H), 5.39 (s,2H), 2.29 (s, 3H); ES-LRMS (M+H) m/z 295/297.

Step 2. Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

The compound was prepared essentially as described in Step 2 of example424 using3-bromo-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one.¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J=4.4 Hz), 8.41 (s, 1H), 7.63 (m,2H), 7.41 (dd, 1H, J=5.2 Hz, 4.8 Hz), 7.02 (m, 2H), 6.52 (s, 1H), 5.44(s, 2H), 5.29 (s, 2H), 2.40 (s, 3H); ES-HRMS m/z 421.0355/423.0358 (M+Hcalculated for C₁₉H₁₆N₂O₂F₂Br requires 421.0358/423.0339).

Example 435

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-oneStep 1. Preparation of3-bromo-4-hydroxy-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one

Commercially available 4-hydroxy-6-methyl pyrone (5 g, 39.6 mmol) wascondensed with commercially available 2-(aminomethyl)pyridine (4.03 mL,39.6 mmol) in water (25 mL). The mixture was heated in an oil bath atreflux for 1.5 hour under nitrogen. The solvent was evaporated. MS and¹H-NMR were consistent with the desired desbromonated structure. ¹H NMR(CD₃OD, 400 MHz) δ8.47 (d, 1H, J=4.8 Hz), 7.75 (ddd, 1H, J=2.0 Hz, 1.6Hz, 1.6 Hz), 7.28 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.11 (d, 1H, J=7.6 Hz),5.98 (d, 1H, J=2.4 Hz), 5.77 (d, 1H, J=2.4 Hz), 5.35 (s, 2H), 2.28 (s,3H); ES-LRMS (M+H) m/z 217.

To a suspension of the above compound (3.0 g, 13.8 mmol) in MeCl₂ (30mL) was added NBS (2.71 g, 15.18 mmol). The reaction mixture stirred atroom temperature for 2.5 hours under nitrogen. The suspension waschilled in an ice bath and filtered. The solid was washed with freshMeCl₂ and dried to afford a beige solid (3.18 g, 77%) after drying.¹H-NMR (CD₃OD, 400 MHz) δ 8.46 (d, 1H, J=4.8 Hz), 7.76 (ddd, 1H, J=2.0Hz, 1.6 Hz, 1.6 Hz), 7.29 (dd, 1H, J-5.2 Hz, 5.2 Hz), 7.17 (d, 1H, J=8.0Hz), δ 07 (s, 1H), 5.40 (s, 2H), 2.30 (s, 3H); ES-LRMS (M+H) m/z295/297.

Step 2. Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one

The compound was prepared essentially as described in Step 2 of example424 using3-bromo-4-hydroxy-6-methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H)-one¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J=4.4 Hz), 7.76 (ddd, 1H, J=2.0Hz, 2.0 Hz, 1.6 Hz), 7.62 (q, 1H), 7.29 (dd, 1H, J=5.2 Hz, 5.6 Hz), 7.21(d, 1H, J=8.0 Hz), 7.04 (m, 2H), 6.51 (s, 1H), 5.45 (s, 2H), 5.29 (s,2H), 2.42 (s, 3H); ES-HRMS m/z 421.0354/423.0332 (M+H calculated forC₁₉H₁₆N₂O₂F₂Br requires 421.0358/423.0339).

Examples 425-427, 429-435, 436-437

The following compounds were prepared essentially according to theprocedures set forth above for Example 424, using the products of Step 1of Examples 424, 428, or 435.

M + H m/z ES-HRMS Ex.No. R₁ R₂ R₃ R₄ R₅ X Y Z MF required m/z 425 H H FH H N CH CH C₁₉H₁₆N₂O₂FBr 403.0452/ 403.0444/ 405.0434 405.0414 426 F HF H F N CH CH C₁₉H₁₄N₂O₂F₃Br 439.0264/ 439.0270/ 441.0245 441.0274 427 FH H H F N CH CH C₁₉H₁₅N₂O₂F₂Br 421.0358/ 421.0378/ 423.0339 423.0368 429H H F H H CH N CH C₁₉H₁₆N₂O₂FBr 403.0487/ 403.0487/ 405.0438 405.0438430 F H F H F CH N CH C₁₉H₁₄N₂O₂F₃Br 439.0264/ 439.0267/ 441.0245441.0241 431 F H H H H CH N CH C₁₉H₁₆N₂O₂FBr 403.0452/ 403.0489/405.0434 405.0474 432 F H F F H CH N CH C₁₉H₁₄N₂O₂F₃Br 439.0264/439.0266/ 441.0245 441.0231 433 F H Cl H H CH N CH C₁₉H₁₅N₂O₂FC1Br437.0062/ 437.0068/ 439.0041 439.0041 434 Cl H F H H CH N CHC₁₉H₁₅N₂O₂FC1Br 437.0062/ 437.0048/ 439.0041 439.0043 435 F H H H F CH NCH C₁₉H₁₅N₂O₂F₂Br 421.0358/ 421.0371/ 423.0339 423.0336 436 H H F H H CHCH N C₁₉H₁₆N₂O₂FBr 403.0452/ 403.0454/ 405.0434 405.0379 437 F H F H FCH CH N C₁₉H₁₄N₂O₂F₃Br 439.0264/ 439.0266/ 441.0245 441.0242 438 F H F FH CH CH N C₁₉H₁₄N₂O₂F₃Br 439.0264/ 439.0264/ 441.0245 441.0241

NMR characterization of compounds of Examples 425-427, 429-435, 436-437Ex. No. NMR Data 425 ¹H-NMR (CD₃OD, 400 MHz) δ 8.47 (d, 2H, J = 5.6 Hz),7.50 (q, 2H), 7.14 (m, 4H), 6.49 (s, 1H), 5.44 (s, 2H), 5.27 (s, 2H),2.32 (s, 3H 426 ¹H-NMR (CD₃OD, 400 MHz) δ 8.48 (dd, 2H, J = 1.6 Hz),7.15 (d, 2H, J = 6.0 Hz), 6.98 (t, 2H, J = 1.2 Hz), 6.60 (s, 1H), 5.45(s, 2H), 5.29 (s, 2H), 2.36 (s, 3H) 427 ¹H NMR (CD₃OD, 400 MHz) δ 8.47(d, 2H, J = 1.6 Hz), 7.45 (m, 1H), 7.16 (d, 2H, J = 5.6 Hz), 7.06 (t,2H, J = 8.4 Hz), 6.62 (s, 1H), 5.46 (s, 2H), 5.34 (s, 2H), and 2.37 (s,3H) 429 ¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 4.4 Hz), 8.40 (s,1H), 7.62 (d, 1H, J = 8.0 Hz), 7.49 (q, 2H), 7.41 (dd, 1H, J = 4.8 Hz,4.8 Hz), 7.14 (t, 2H, J = 8.8 Hz), 6.46 (s, 1H), 5.43 (s, 2H), 5.26 (s,2H), 2.38 (s, 3H) 430 ¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 3.6Hz), 8.42 (d, 1H, J = 1.2 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.41 (dd, 1H, J= 5.2 Hz, 4.8 Hz), 6.97 (m, 2H), 6.57 (s, 1H), 5.45 (s, 2H), 5.27 (s,2H), 2.42 (s, 3H) 431 ¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 4.4Hz), 8.41 (d, 1H, J = 1.6 Hz), 7.58 (m, 2H), 7.41 (m, 2H), 7.22 (m, 2H),6.51 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 2.39 (s, 3H) 432 ¹H-NMR(CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 4.0 Hz), 8.41 (d, 1H, J = 1.6 Hz),7.63 (d, 1H, J = 7.6 Hz), 7.53 (m, 1H), 7.41 (dd, 1H, J = 5.6 Hz, 5.2Hz), 7.26 (m, 1H), 6.51 (s, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 2.40 (s,3H) 433 ¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 4.0 Hz), 8.41 (d, 1H,J = 1.6 Hz), 7.60 (m, 2H), 7.39 (dd, 1H, J = 5.2 Hz), 7.28 (s, 1H), 7.26(s, 1H), 6.50 (s, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 2.40 (s, 3H) 434¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (d, 1H, J = 4.0 Hz), 8.41 (d, 1H, J = 1.6Hz), 7.68 (m, 2H), 7.39 (dd, 1H, J = 4.8 Hz, 4.8 Hz), 7.31 (dd, 1H, J =2.4 Hz, 2.8 Hz), 7.16 (dd, 1H, J = 2.8 Hz, 2.8 Hz, 2.8 Hz), 6.50 (s,1H), 5.45 (s, 2H), 5.32 (s, 2H), 2.41 (s, 3H) 435 ¹H-NMR (CD₃OD, 400MHz) δ 8.45 (d, 1H, J = 4.0 Hz), 8.42 (s, 1H), 7.60 (d, 1H, J = 8.0 Hz),7.47 (m, 1H), 7.40 (dd, 1H, J = 5.2 Hz, 4.8 Hz), 7.07 (m, 2H), 6.59 (s,1H), 5.45 (s, 2H), 5.32 (s, 2H), 2.41 (s, 3H) 436 ¹H-NMR (CD₃OD, 400MHz) δ 8.45 (d, 1H, J = 4.8 Hz), 7.76 (ddd, 1H, J = 2.0 Hz, 1.6 Hz, 1.6Hz), 7.51 (q, 2H), 7.30 (dd, 1H, J = 5.2 Hz), 7.19 (d, 1H, J = 7.6 Hz),7.14 (t, 2H, J = 8.8 Hz), 6.46 (s, 1H), 5.44 (s, 2H), 5.26 (s, 2H), 2.40(s, 3H) 437 ¹H-NMR (CD₃OD, 400 MHz) δ 8.46 (d, 1H, J = 4.8 Hz), 7.76(ddd, 1H, J = 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.29 (dd, 1H, J = 4.8 Hz, 5.2Hz), 7.21 (d, 1H, J = 7.6 Hz), 6.69 (dd, 2H, J = 8.0 Hz, 7.6 Hz), 6.57(s, 1H), 5.46 (s, 2H), 5.28 (s, 2H), 2.43 (s, 3H) 438 ¹H-NMR (CD₃OD, 400MHz) δ 8.45 (d, 1H, J = 4.4 Hz), 7.76 (ddd, 1H, J = 2.0 Hz, 1.6 Hz, 1.6Hz), 7.55 (m, 1H), 7.26 (m, 3H), 6.50 (s, 1H), 5.46 (s, 2H), 5.29 (s,2H), 2.42 (s, 3H)

Example 439

3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-oneStep 1. Preparation of3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a chilled suspension (−30° C.) of3-bromo-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one(0.481 g, 1.63 mmol) in dichloromethane (6 mL) was added triethylamine(0.28 mL, 2.04 mmol), followed by the addition of a solution oftrifluoromethanesulfonic anhydride (0.4 mL, 2.44 mmol) indichloromethane (3 mL). The reaction mixture stirred at −30° C. undernitrogen for 1 hour. The reaction mixture was diluted withdichloromethane and washed with cold NaHCO₃/water. The organic extractswere dried over Na₂SO₄ and the filtrate was concentrated under reducedpressure to afford the desired compound as a yellow semisolid (0.6675 g,95%) after drying. ES-LRMS (M+H) m/z 427.1/429.1.

Step 2. Preparation of3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

To a degassed solution of3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA(0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) andPdCl₂(PPh₃)₂ (0.11 g) were added. The reaction mixture stirred at roomtemperature under nitrogen for 1 hour and then heated in an oil bath(65° C.) under nitrogen overnight. The solvents were distilled in vacuoand the residue was purified by flash column chromatography (5% methanolin ethyl acetate). The extracts were concentrated to afford the desiredcompound (0.432 g, 69%) after drying. ¹H-NMR (CD₃OD, 400 MHz) δ 8.45 (s,2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18(t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z397.0361/399.0310 (M+H calculated for C₂₀H₁₅N₂OFBr requires397.0346/399.0328).

Step 3. Preparation of3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

A suspension of3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one(0.430 g, 1.01 mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containingPtO₂ (0.015 g) was stirred in an atmosphere of hydrogen (15 psi) in aFischer-Porter bottle for 2 hours. The reaction mixture was filtered andthe filtrate was concentrated to reduce volume. The material waspurified by flash column chromatography (ethyl acetate). The appropriatefractions were combined and concentrated under reduced pressure toafford the desired product (0.0943 g, 22%) as a sticky semisolid afterdrying. ¹H-NMR (CD₃OD, 400 MHz) δ 8.46 (d, 2H, J=26.4 Hz), 7.60 (d, 1H,J=8.0 Hz), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.21 (m, 2H), 6.97 (t, 2H,J=8.8 Hz), 6.24 (s, 1H), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H);ES-HRMS m/z 401.0645/403.0603 (M+H calculated for C₂₀H₁₉N₂OFBr requires401.0659/403.0641).

Example 440

3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for step 1 to step 3 (0.374 g, 25%). MS and ¹H-NMR for step 1were consistent with the desired structure. ¹H-NMR (CD₃OD, 400 MHz) δ8.80 (d, 2H, J=6.8 Hz), 7.89 (d, 2H, J=6.8 Hz), 6.61 (s, 1H), 5.66 (s,2H), 2.45 (s, 3H); ES-HRMS m/z 427.9645/429.9625 (M+H calculated forC₁₃H₁₁N₂O₄SF₃Br requires 427.9599/429.9578).

MS and ¹H-NMR for step 3 were consistent with the desired structure.¹H-NMR (CD₃OD, 400 MHz) δ 8.48 (d, 2H, J=5.2 Hz), 7.21 (m, 2H), 7.13 (d,2H, J=5.2 Hz), 6.98 (t, 2H, J=9.0 Hz), 6.26 (s, 1H), 5.43 (s, 2H), 2.95(m, 4H), 2.25 (s, 3H); ES-HRMS m/z 401.0682/403.0636 (M+H calculated forC₂₀H₁₉N₂OFBr requires 401.0659/403.0641).

Example 441

3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-oneStep 1. Preparation of3-chloro-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

To a suspension of4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (1.016 g, 4.7mmol) in MeCl₂ (10 mL) was added NCS (1.21 g, 1.78 mmol). The reactionmixture stirred at room temperature for 24 hours under nitrogen. Thesuspension was chilled in an ice bath and filtered. The solid was washedwith fresh MeCl₂ and dried to afford a yellow solid (1.00 g, 85%) afterdrying. ¹H-NMR (CD₃OD, 400 MHz) δ 8.54 (m, 2H), 7.85 (d, 1H, J=1.6 Hz),7.61 (m, 1H), 6.10 (s, 1H), 5.41 (s, 2H), 2.33 (s, 3H); ES-LRMS (M+H)m/z 251/253.

Step 2. Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

To a degassed cold solution of DMF (10 mL) and PPh₃ (resin, 2.2 g, 6.6mmol) was added DEAD (1.038 mL, 6.6 mmol). The reaction mixture stirredat −10° C. for 20 minutes under nitrogen. A solution of3-chloro-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one(1.00 g, 4.0 mmol) and 2,4-difluorobenzylalcohol (0.66 mL, 6.0 mmol) inDMF (10 mL) was added to the resin suspension. The reaction mixturestirred at −10° C. for 30 minutes and then allowed to stir at roomtemperature for 1 hour. The resin was filtered and rinsed with freshMeOH and the filtrate concentrated. The residue was dissolved in ethylacetate and purified by flash column chromatography (5% methanol inethyl acetate). The appropriate fractions were concentrated. ¹H-NMR(CD₃OD, 400 MHz) δ 8.45 (ddd, 2H, J=1.6 Hz, 1.6 Hz, 1.6 Hz), 7.61 (m,2H), 7.41 (dd, 1H, J=4.4 Hz, 4.8 Hz), 7.02 (m, 2H), 6.55 (s, 1H), 5.43(s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m/z 377.0882/379.0840 (M+Hcalculated for C₁₉H₁₆N₂O₂F₂Cl requires 377.0863/379.0840).

Example 442

1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin-2(1H)-onetrifluoroacetate

The title compound was prepared by a procedure similar to the onedescribed for Example 385, step 2 (0.142 g, 9%). ¹H NMR (CD₃OD, 400 MHz)δ 7.64 (s, 1H), 7.00 (m, 2H), 6.66 (s, 1H), 5.29 (s, 2H), 5.18 (s, 2H),2.50 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 469.0488/471.0464 (M+Hcalculated for C₁₉H₁₇N₄O₂F₃Br requires 469.0481/471.0463).

Example 443

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-methyl4-(methylamino)pyrimidin-5-yl]methyl}pyridin-2(1H)-one trifluoroacetate

To a solution of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride (0.15 g, 0.3 mmol) in DMF (3 mL) was added DBU (0.09 mL,0.6 mmol). The solution was cooled in an ice bath and iodomethane (0.019mL, 0.3 mmol) was added. The reaction mixture stirred at roomtemperature under nitrogen for 2 hours. The reaction was purified byreverse phase HPLC 10-90% CH₃CN/water (30 minute gradient) at a flowrate of 100 mL/min. The appropriate fractions (m/z=465 M+H) werecombined and freeze dried to afford the desired product (0.036 g, 25%)as a white powder. ¹H NMR (CD₃OD, 400 MHz) δ 7.72 (s, 1H), 7.60 (m, 1H),7.03 (m, 2H), 6.62 (s, 1H), 5.31 (s, 2H), 5.16 (s, 2H), 3.77 (s, 3H),2.60 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 465.0717/467.0712 (M+Hcalculated for C₂₀H₂₀N₄O₂F₂Br requires 465.0732/467.0714).

Example 444

ethylN-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)glycinatetrifluoroacetate

The title compound was prepared by a procedure similar to the onedescribed for Example 442 with the exception that the reaction mixturehad to be heated at oil bath temperature 70° C. for 2 days (0.1384 g,51%). ¹H NMR (CD₃OD, 400 MHz) δ 7.78 (s, 1H), 7.61 (m, 1H), 7.03 (m,2H), 6.61 (s, 1H), 5.30 (s, 2H), 5.18 (s, 2H), 5.03 (s, 2H), 4.27 (q,2H), 2.55 (s, 3H), 2.46 (s, 3H), 1.28 (t, 3H, J=7.0 Hz); ES-HRMS m/z537.0936/539.0932 (M+H calculated for C₂₃H₂₄N₄O₄F₂Br requires537.0943/539.0926).

Example 445

N-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)-2-hydroxyacetamidetrifluoroacetate

To a chilled solution of1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate (0.200 g, 0.38 mmol) in DMF (20 mL) and a catalyticamount of DMAP was added triethylamine (0.064 mL, 0.38 mmol). Thereaction stirred at −20° C. and acetoxyacetyl chloride (0.082 mL, 0.76mmol) was added. The reaction stirred cold for 15 minutes and thenallowed to warm up to room temperature for 3 hours. The reaction wasmonitored by LR-ESMS m/z=466. The reaction was incomplete after 3 hours.Added acetoxyacetyl chloride (0.05 mL, 0.466 mmol), and triethylamine(0.2 mL, 1.43 mmol) to the reaction mixture and continued to stirovernight at room temperature. The next morning the reaction heated at65° C. for 3 hours. The solvent was removed in vacuo and 1N LiOH (2.5mL) was added to the residue. The reaction was heated at 60° C. for 5hours. The reaction was diluted with acetonitrile and water (1:1) andpurified by reverse phase HPLC in 10-90% CH₃CN/water (30 minutegradient) at a flow rate of 50 mL/min. The appropriate fractions werefreeze dried to afford the desired product (0.020 g, 9%). ¹H NMR (CD₃OD,400 MHz) δ 8.04 (s, 1H), 7.6 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 5.30(s, 2H), 5.24 (s, 2H), 4.26 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMSm/z 465.1161 (M+H calculated for C₂₁H₂₀N₄O₄F₂Cl requires 465.1136).

Example 446

3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-oneStep 1. Preparation of3-chloro-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one

To a solution of4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one(1.00 g, 4.3 mmol) in glacial acetic acid (10 mL) was added NCS (0.79 g,5.94 mmol). The reaction mixture stirred at 60° C. for 6 hours. Thesolvent was removed under reduced pressure and the resulting residue wastriturated with ethyl acetate. The desired product was filtered anddried (0.80 g, 69%). ¹H NMR (CD₃OD, 400 MHz) δ 8.47 (s, 1H), 8.42 (s,1H), 6.08 (s, 1H), 5.36 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z266.0691 (M+H calculated for C₁₂H₁₃N₃O₂Cl requires 266.0691).

Step 2. Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one

To a solution of 3-chloro-4-hydroxy-6-methyl-1-[(5methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (2.48 g, 9.3 mmol) in DMA (7mL)was added K₂CO₃ (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzylbromide (1.2 mL, 9.3 mmol). The reaction mixture stirred at roomtemperature under nitrogen for 1.5 hours. The solvent was distilled invacuo. The resulting residue was diluted in dichloromethane and washedwith water. The organic extracts were concentrated and the resultingresidue was purified by flash column chromatography (ethyl acetate). Theappropriate fractions were combined, and concentrated. ¹H NMR (CD₃OD,400 MHz) δ 8.49 (d, 1H, J=1.2 Hz), 8.40 (s, 1H), 7.59 (m, 1H), 7.04 (m,2H), 6.54 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 2.54 (s, 3H), 2.40 (s,3H); ES-HRMS m/z 392.1014 (M+H calculated for C₁₉H₁₇N₃O₂ClF₂ requires392.0972).

Example 447

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-onetrifluoroacetate

To a suspension of3-bromo-1-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(0.25 g, 0.53 mmol) in THF was added methylamine (1 mL, 2.1 mmol). Thereaction was sealed and stirred at room temperature overnight. Thereaction mixture was diluted in water:acetonitrile (1:1) and purified byreverse phase HPLC 10-90% CH₃CN/water (30 minute gradient) at a flowrate of 70 mL/min. The appropriate fractions were combined and freezedried to afford the desired product (0.22 g, 71%) as an amorphous solid.¹H NMR (CD₃OD, 400 MHz) δ 8.73 (s, 1H), 8.55 (s, 1H), 7.6 (m, 2H), 7.02(m, 1H), 6.54 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 4.37 (s, 2H), 2.78(s, 3H), 2.56 (s, 3H). ES-HRMS m/z 465.0732/467.0709 (M+H calculated forC₂₀H₂₀N₄O₂BrF₂ requires 465.0732/467.0714).

Example 448

Ethyl5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate

To a mixture of3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.59 g,2.07 mmol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (0.62 g, 2.4mmol) in THF (15 mL) was added NaH (0.06 g, 2.4 mmol). The reactionstirred at 60° C. for 3.5 hours. The solvent was removed under reducedpressure and the residue was partitioned over dichloromethane and citricacid (5%). The organic extracts were washed with water and dried overNa₂SO₄ (anhydrous). The organic extracts were concentrated and theresidue was purified by flash column chromatography (100% ethylacetate). The appropriate fractions were combined and concentrated underreduced pressure to remove solvent. ¹H NMR (CD₃OD, 400 MHz) δ 9.11 (d,1H, J=1.6 Hz), 8.77 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H),5.53 (s, 2H), 5.30 (s, 2H), 4.49 (q, 2H), 2.52 (s, 3H), 1.39 (t, 3H,J=7.2 Hz); ES-HRMS m/z 450.1045 (M+H calculated for C₂₁H₁₉N₃O₄ClF₂requires 450.01027).

Example 449

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one

To a suspension of ethyl5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) inTHF:t-butanol (1:1) (10 mL) was added NaBH₄ (0.46 g, 12.4 mmol). Thereaction stirred at room temperature under argon overnight. The reactionmixture was quenched with acetic acid (2 mL) and the solvent was removedin vacuo. The residue was triturated with water and filtered. The solidwas washed with fresh water followed by ethanol. The solid was purifiedby flash column chromatography (100% ethyl acetate). The appropriatefractions were combined and concentrated under reduced pressure toafford the desired compound (1.58 g, 44%) as a white solid. ¹H NMR(CD₃OD, 400 MHz) δ 8.59 (s, 1H), 8.56 (s, 1H), 7.52 (m, 1H), 7.01 (m,2H), 6.55 (m, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.71 (2H), 2.54 (s, 3H);ES-HRMS m/z 408.0940 (M+H calculated for C₁₉H₁₇N₃O₃ClF₂ requires408.0921).

Example 450

5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylpyrazine-2-carboxamide

To a cold solution of5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid (0.175 g, 0.37 mmol) in DMF (5 mL, −10° C.) was added IBCF (0.046mL, 0.35 mmol) followed by NMM (0.041 mL 0.37 mmol). The reaction wasactivated for 20 minutes at −15° C. after which dimethylamine (0.375 mL,0.74 mmol) was added. The reaction stirred at −10° C. to roomtemperature for 45 minutes. The solvent was removed in vacuo and theresidue was purified by reverse phase HPLC 10-90% CH₃CN/water (30 minutegradient) at a flow rate of 70 mL/min. The appropriate fractions werecombined and freeze dried to afford the desired product (0.140 g, 75%)as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 8.68 (s, 1H), 8.67 (s, 1H),7.52 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H),3.11 (s, 3H), 3.07 (s, 3H), 2.55 (s, 3H); ES-HRMS m/z 493.0680/495.0657(M+H calculated for C₂₁H₂₀N₄O₃BrF₂ requires 493.0680/495.0657).

Example 451

5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-methylpyrazine-2-carboxamide

The title compound was prepared essentially as in Ex. 450, substitutingdimethylamine with methylamine. ¹H NMR (CD₃OD, 400 MHz) δ 9.07 (s, 1H),8.68 (s, 1H), 7.54 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.52 (s, 2H),5.30 (s, 2H), 2.94 (s, 3H), 2.54 (s, 3H); ES-HRMS m/z 479.0542/481.0518(M+H calculated for C₂₀H₁₈N₄O₃BrF₂ requires 479.0525, 481.0507).

Example 452

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(1-hydroxy-1-methylethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one

To a cold flask of MeMgBr (1.59 mL, 1.0 mmol) was added a suspension ofethyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate(0.5 g, 1.0 mmol) in THF (20 mL). The reaction stirred at 0° C. for 1.5hours and then at room temperature overnight. The reaction was quenchedwith cold citric acid (25 mL, 5%) and extracted with ethyl acetate(2×100 mL). The organic extracts were washed with fresh water. Theorganic extracts were concentrated and purified by reverse phase HPLC10-90% CH₃CN/water (30 minute gradient) at a flow rate of 70 mL/min. Theappropriate fractions were combined and freeze dried to afford thedesired product (29.9 mg, 6%). ¹H NMR (CD₃OD, 400 MHz) δ 8.76 (d, 1H,J=1.6 Hz), 8.54 (d, 1H, J=1.2 Hz), 7.52 (m, 1H), 7.02 (m, 2H), 6.52 (s,1H), 5.45 (s, 2H), 5.29 (s, 2H), 2.55 (s, 3H), 1.52 (s, 6H); ES-HRMS m/z480.0745/482.0722 (M+H calculated for C₂₁H₂₁N₃O₃BrF₂ requires480.0729/482.0711).

Example 453

5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-methoxyethyl)pyrazine-2-carboxamide

The title compound was prepared essentially as in Ex. 450, substitutingdimethylamine with 2-methoxyethylamine. ¹H NMR (CD₃OD, 400 MHz) δ 9.08(d, 1H, J=1.2 Hz), 8.70 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.04 (m, 2H),6.54 (s, 1H), 5.53 (s, 2H), 5.30 (s, 2H), 3.56 (m, 4H), 3.30 (s, 3H),2.54 (s, 3H); ES-HRMS m/z 523.0822/525.0810 (M+H calculated forC₂₂H₂₂N₄O₄BrF₂ requires 523.0787/525.0770).

Example 454

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[5-(morpholin-4-ylcarbonyl)pyrazin-2-yl]methyl}pyridin-2(1H)-one

The title compound was prepared essentially as in Ex. 450, substitutingdimethylamine with morpholine. ¹H NMR (CD₃OD, 400 MHz) δ 8.77 (d, 1H,J=1.6 Hz), 8.67 (s, 1H), 7.54 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.50(s, 2H), 5.30 (s, 2H), 3.75 (s, 4H), 3.59 (dd, 4H, J=5.6 Hz, 5.2 Hz),2.55 (s, 3H); ES-HRMS m/z 535.0816/537.0817 (M+H calculated forC₂₃H₂₂N₄O₄BrF₂ requires 535.0787/537.0770).

Example 455

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(4-hydroxypiperidin-1-yl)carbonyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-oneStep 1. Preparation of5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid

A mixture of ethyl5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate(1.03 g, 2.3 mmol) in 1N NaOH (3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v)stirred at room temperature for 2 hours. The reaction mixture wasquenched with 5% citric acid and filtered. The solid was washed withwater and dried to afford the desired product (1.011 g, 100%) as a whitesolid. ¹H NMR (CD₃OD, 400 MHz) δ 9.02 (s, 1H), 8.60 (s, 1H), 7.60 (m,1H), 7.04 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.52 (s,3H); ES-HRMS m/z 422.0732 (M+H calculated for C₁₉H₁₅N₃O₄ClF₂ requires422.0714).

Step 2. Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(4-hydroxypiperidin-1-yl)carbonyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for Example 453 (0.1396 g, 47%). ¹H NMR (CD₃OD, 400 MHz) δ8.67 (s, 2H), 7.59 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.49 (s, 2H),5.30 (s, 2H), 4.16 (m, 1H), 3.89 (septet, 1H), 3-72 (m, 1H), 3.38 (m,2H), 2.56 (s, 3H), 1.93 (m, 1H), 1.83 (m, 1H), 1.45 (m, 2H); ES-HRMS m/z505.1485 (M+H calculated for C₂₄H₂₄N₄O₄ClF₂ requires 505.1449).

Example 456

5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(3-hydroxy-2,2-dimethylpropyl)pyrazine-2-carboxamide

The title compound was prepared by a procedure similar to the onedescribed for Example 455 (0.215 g, 71%). ¹H NMR (CD₃OD, 400 MHz) δ 9.08(d, 1H, J=1.2 Hz), 8.71 (d, 1H, J=1.6 Hz), 7.58 (m, 1H), 7.02 (m, 2H),6.57 (s, 1H), 5.52 (s, 1H), 5.30 (s, 1H), 3.31 (s, 4H), 2.55 (s, 3H),0.912 (s, 6H); ES-HRMS m/z 507.1630 (M+H calculated for C₂₄H₂₆N₄O₄ClF₂requires 507.1605).

Example 457

5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide

The title compound was prepared by a procedure similar to the onedescribed for Example 455 except no purification was required, only aNaHCO₃/ethyl acetate extraction was needed (0.2176 g, 73%). ¹H NMR(CD₃OD, 400 MHz) δ 9.11 (d, 1H, J=1.6 Hz), 8.73 (d, 1H, J=1.3 Hz), 7.59(m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.53 (s, 2H), 5.30 (s, 2H), 4.01(q, 2H), 2.54 (s, 3H); ES-HRMS m/z 503.0930 (M+H calculated forC₂₁H₁₇N₄O₃ClF₅ requires 503.0904).

Example 458

1-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Step 1: 1-allyl-4-hydroxy-6-methylpyridin-2(1H)-one.4-hydroxy-6-methyl-2-pyrone (2 g, 16 mmol) was stirred in water (25 mL).Allylamine (1.2 ml, 16 mmol) was added to the reaction. The reaction wasthen heated to 100° C. at which point the reaction became homogeneous.The reaction was stirred at 100° C. for 2 h. The reaction was thenallowed to cool to rt after which a white precipitate formed. Theprecipitate was isolated by suction filtration. After additional washingwith water, 1.8 g (69%) of an off-white solid was obtained.

Step 2: 1-allyl-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one.To a stirred solution of the above pyrone (4.0 g, 24 mmol) in DMF (75ml) was added Cs₂CO₃ (7.8 g, 24 mmol) followed by addition of2,4-difluororbenzyl bromide (3.4 mmol, 26.4 mmol). The resulting mixturewas stirred at rt for 2 h. Additional Cs₂CO₃ (1 g) and bromide (1 ml)was added and the reaction was stirred for an additional 2 h. The Cs₂CO₃was removed by suction filtration. The DMF was removed under vacuum andthe crude material was purified by flash chromatography. Elution withethyl acetate-hexanes (2:1 to 1:1) afforded 1.5 g (21%) of the desiredcompound.

Step 3:1-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(III)-one.To a stirred suspension of the above pyridinone (1 g, 3.4 mmol) in CH₃CN(10 ml) was added n-bromosuccinimide (670 mg, 3.8 mmol). The reactionmixture was stirred, at rt, for 3 h. The product was obtained byfiltration of the reaction mixture and washing of the solid with diethylether. ¹H-NMR (DMSO_(d6)/400 MHz) δ 7.62 (app q, J=8.8 hz, 1H), 7.31(ddd, J=12.0, 9.6, 2.8 hz, 1H); 7.15 (app dtd, J=8.4, 2.4, 0.8 Hz, 1H);6.50 (s, 1H); 5.87 (ddt, J=12.4, 10.4, 5.6 Hz, 1H), 5.30 (s, 2H), 5.10(dd, J=10, 1.6 Hz, 1H), 4.87 (dd, J=17.6, 1.6 Hz, 1H), 4.64 (m, 2H),2.34 (s, 3H); ¹⁹F-NMR (DMSO-d₆/282.2 MHz)-109.68 (quin, J=1H), −113.66(quar, J=1H); HRMS m/z 370.0255 (M+H calcd for C₁₆H₁₅BrF₂NO₂=370.0246).

Example 459

1-allyl-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Step 1: 1-allyl-3-chloro-4-hydroxy-6-methylpyridin-2(1H)-one. To astirred solution of 1-allyl-4-hydroxy-6-methylpyridin-2(1H)-one (500 mg,3.0 mmol) in CH₃CN (10 ml), at rt, was added sequentiallyn-bromosuccinimide (440 mg, 3.3 mmol) and dichloroacetic acid (546 μl,6.62 mmol). The resulting mixture was stirred for 2 h. The heterogeneousmixture was filtered and the solid was washed with additional CH₃CN togive 350 mg (59%) of the desired product as a tan solid. ¹H-NMR(DMSO_(d6)/300 MHz) δ 11.16 (s, 1H), 5.98-5.86 (m, 2H), 5.12 (dd,J=10.5, 1.5 Hz, 1H), 4.89 (dd, J=17.1, 1.5 Hz, 1H), 4.63-4.61 (m, 2H),2.29 (s, 3H). ES-HRMS m/z 200.050 (M+H calcd for C₉H₁₁ClNO₂=200.0470)

Step 2:1-allyl-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one.The title compound was prepared by the procedure outline in thesynthesis of Example 458, step 3. ¹H-NMR (DMSO_(d6)/300 MHz) δ 7.67 (appq, J=8.4 hz, 1H), 7.36 (app dt, J=10.2, 2.7 hz, 1H); 7.15 (m, 1H); 6.58(s, 1H); 5.93 (ddt, J=15.3, 9.6, 4.8 Hz, 1H), 5.30 (s, 2H) 5.15 (dd,J=10.2, 1.2 Hz, 1H), 4.92 (dd, J=17.4, 1.2 Hz, 1H), 4.69-4.67 (m, 2H),2.41 (s, 3H). ES-HRMS m/z 326.0760 (M+H calcd forC₁₆H₁₅ClF₂NO₂=326.0790).

Example 460

Methyl(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]but-2-enoate

To a stirred suspension of NaH (277 mg, 11 mmol) in anhydrous THF (30ml), which was cooled to 0° C., was slowly added3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (3.3 g, 10mmol). The resulting slurry was stirred for 15 min, after which methyl4-bromocrotonate (1.4 ml, 12 mmol) was added to the reaction. The icebath was removed and the reaction was heated to reflux for 16 h. Thereaction was quenched by the addition of 1N NH₄Cl. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (5×). Theorganics were combined, dried, and concentrated in vacuo. The crudeyellowish material was then triturated with Et₂O to give, afterfiltration and drying, 1.8 g (43%) of a white solid. ¹H-NMR(DMSO_(d6)/300 MHz) δ 7.65 (app q, J=8.7 hz, 1H), 7.36 (app dt, J=12.0,3.0 hz, 1H); 7.17 (dt, J=8.4, 1.8 Hz, 1H); 6.94 (dt, J=15.9, 4.5 Hz,1H); 6.57 (s, 1H), 5.52 (d, J=15.9 Hz, 1H), 5.29 (s, 2H), 4.84 (m, 2H),3.63 (s, 3H), 2.33 (s, 3H). ES-HRMS m/z 428.0301 (M+H calcd forC₁₈H₁₇BrF₂NO₄=428.0310).

Example 461

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one

Step 1:4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one. Thetitle compound was prepared by alkylation of4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2.5 g, 10 mmol)with propargyl bromide (1.3 ml, 11.0 mmol) as described above to give1.39 (44%) of the desired product. ¹H-NMR (DMSO_(d6)/300 MHz) δ 7.60(app q, J=8.4 hz, 1H), 7.35-7.27 (m, 1H); 7.16-7.10 (m, 1H); 5.94 (d,J=2.1 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.03 (s, 2H), 4.76 (d, J=2.4, Hz,2H), 3.31 (s, 3H), 3.24 (t, J=2.4 Hz, 1H), 2.39 (s, 3H); ES-HRMS m/z290.0994 (M+H calcd for C₁₆H₁₄F₂NO₂=290.0993).

Step 2: Bromination of4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-prop-2-ynylpyridin-2(1H)-one (500mg, 1.67 mmol) with NBS (300 mg, 1.67 mmol) was carried out in themanner described above to give 350 mg (57%) of the desired compound.¹H-NMR (DMSO-d₆/300 MHz) δ 7.67 (app q, J=9.0 hz, 1H), 7.36 (app dt,J=10.5, 2.4 hz, 1H); 7.23-7.16 (m, 1H); 6.60 (s, 1H), 5.29 (s, 2H), 4.90(d, J=2.4, Hz, 1H), 3.35 (s, 3H), 3.32 (s, 1H), 2.53 (s, 3H); ES-HRMSm/z 368.0107 (M+H calcd for C₁₁H₁₃BrF₂NO₂=368.0098).

Example 462

4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1(pyridin-3-ylmethyl)pyridin-2(1H)-one

Step 1: To a suspension of(4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one)(710 mg, 2 mmol) in dioxane (10 mL) was added selenium dioxide (1.1 g 10mmol). The resulting mixture was heated to 160° C. in a 125 mL sealedtube for 1 h. The reaction was filtered through a fritted funnel. Thefiltrate was washed with (10:1) CH₂Cl₂-MeOH. The organics were combinedand concentrated in vacuo. The crude material was purified by flashchromatography. Elution with (50:50→0:100)hexanes yielded 450 mg (63%)of the aldehyde. ¹H-NMR (DMSO_(d6)/400 MHz). δ9.48 (s, 1H, CHO).

Step 2: The aldehyde (350 mg, 1 mmol) was dissolved in MeOH (4 mL) andcooled to 0° C. To this mixture was added NaBH₄ (28 mg, 1 mmol) in oneportion. After 30 min, additional NaBH₄ (20 mg) was added to thereaction. The MeOH was then removed under vacuum. The residue wasdiluted with 1N NH₄Cl and then extracted with CH₂Cl₂(4×). The organicswere combined, dried, and concentrated in vacuo. The yellowish crudeproduct was then taken up in (1:1) CH₂Cl₂-Et₂O. After sitting for aperiod of time a white precipitate resulted. Filtration and washing withadditional Et₂O yielded, after drying, 250 mg (55%) of the desiredalcohol. ¹H-NMR (DMSO_(d6)/400 MHz). δ8.42 (dd, J=4.4, 1.6 Hz, 1H) 8.37(d, J=1.6 Hz, 1H), 7.61 (app q, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),7.32-7.27 (M, 2H), 7.12 (dt, J=8.4, 1.6 Hz, 1H), 6.07 (d, J=2.8 Hz, 1H),5.99 (d, J=12.8 Hz, 1H), 5.63 (br s, 1H), 5.18 (s, 2H), 5.09 (s, 2H),4.29 (s, 2H). LC/MS, t_(r)=1.19 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z359.1 (M+H)

Example 463

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

The title compound was prepared by bromination of as described above togive a 60% yield. ¹H-NMR (DMSO_(d6)/300 MHz) δ 7.93 (d, J=7.8 Hz, 1H),7.73-7.65 (m, 3H), 7.38 (dt, J=10.2, 2.4 Hz, 1H), 7.21 (app t, J=8.7 Hz,2H), 6.74 (s, 1H), 5.38-5.36 (m, 4H), 4.50 (s, 2H); ES-HRMS m/z 437.0311(M+H cacld for C₁₉H₁₆BrF₂N₂O₂=437.0313).

Example 464

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(dimethylamino)methyl]-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

The title compound was prepared in a similar manner to the procedureoutlined below for3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino)-methyl]pyridin-2(1H)-oneusing the aldehyde (300 mg, 0.85 mmol) described above and 2.0 N THFsolution of dimethylamine (500 μL, 1 mmol) to give 110 mg (34%) of acolorless oil. The oil was then dissolved in MeOH (1 mL) and stirredwith fumaric acid (25 mg) for 1 h. The resulting precipitate wasfiltered, washed with diethyl ether, and dried to give the pure productas it's fumurate salt. ¹H-NMR (DMSO-d₆/400 MHz). δ8.43-8.41 (m, 1H),8.35 (s, 1H), 7.67-7.61 (m, 1H), 7.44-7.40 (m, 1H), 7.35-7.29 (m, 2H),7.17-7.12 (m, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 5.41 (s, 2H), 5.32 (s,2H), 3.13 (s, 2H), 2.12 (s, 6H). LC/MS, t_(r)=1.55 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 464 (M+H).

Example 465

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-oneStep 1:4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2carbaldehyde

In a 300 ml high-pressure glass reaction vessel (16.3 g, 45 mmol) wasdissolved in 1,4-dioxane (90 mL). The reaction vessel was sealed andimmersed in a preheated oil bath at 170° C. The reaction was heated at170° C. (165-170° C.) for 1.5 hours and then cooled to room temperature.The reaction was worked up by filtering the reaction mixture through aplug of celite and silica gel. The plug was then washed with 500 ml ofmethanol-CH₂Cl₂ mixture (1:5). The filtrate was evaporated to give 14.2g of the desired crude aldehyde.

Step 2: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one

In a 500 ml three neck round bottom flask equipped with a stir bar of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde(14.2 g, 37.7 mmol) was dissolved in methanol (200 mL). The reactionmixture was cooled to 0° C. and to this was added sodium borohydride(2.13 g, 56.30 mmol) in a slow portion-wise fashion. The reaction wasstirred at 0° C. for 2 hour. Excess amount of sodium borohydride wasadded to drive the reaction to completion. After stirring forapproximately 2.5 hours, the reaction was allowed to warm to roomtemperature and then concentrated to dryness. The residue was taken upin ethyl acetate (100 mL) and washed with dilute HCl (pH of aqueouslayer was approximately 4). Organic extracts were washed with brine(1×50 ml), dried over MgSO₄, and concentrated in vacuo. The crudeproduct was recrystallized from ethyl acetate and hexane to yield 7.56 g(44% yield-starting from step 1) of the desired alcohol.

Step 3: Preparation of the Title Compound

In a 100 ml round bottom flask of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one(2.49 g, 6.56 mmol), from step 2, was dissolved in acetonitrile (35 mL).The reaction mixture was cooled to 0° C. in ice bath for 10 min. andthen charged with N-bomosuccinamide (1.17 g, 6.6 mmol). The mixture wasallowed to stir, at 0° C., under nitrogen atmosphere for 2 hours. Thereaction was the worked up by removing the acetonitrile under vacuum.The resulting residue was then filtered, with washing from a smallamount of acetonitrile, to give a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.695-7.588-(m, 2H), 7.368-7.314 (m, 3H), 7.175 (dt, J=8.5,2.5, Hz, 1H), 6.760 (s, 1H), 5.712 (t, J=5.674 Hz, 1H), 5.384 (s, 2H),4.004-3.990 (m, 2H); ES-HRMS m/z 458-0013 (M+H-calcd for C₁₉H₁₃BrF₄NO₃,requires 458.0013).

Example 466

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one

The title compound was prepared by taking4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one(1.5 g, 3.9 mmol) in acetonitrile (15 mL) and adding to thatN-chlorosuccinimide (580 mg, 4.3 mmol). The reaction was stirred at rtfor 3 h afterwhich a small amount of additional N-chlorosuccinimide (50mg, 0.4 mmol) was added to the reaction. Stirring was continued for 1 h.The reaction mixture was filtered through a fritted funnel to obtain thecrude material. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69-7.61 (m, 2H), 7.37-7.31(m, 3H), 7.17 (dt, J=8.8, 2.0 Hz, 1H), 6.80 (s, 1H), 5.70 (t, J=6.0 Hz,1H), 5.38 (s, 2H), 4.01 (d, J=6.0 Hz, 2H); ES-HRMS m/z 414.0515 (M+Hcalcd for C₁₉H₁₃ClF₄NO₃, requires 414.0520).

Example 467

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde

Preparation of the title compound. In a 50 ml one neck round bottomflask4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde(0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reactionmixture was cooled to 0° C. in ice bath and charged withN-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was allowed to stirat 0° C. for 2 hours under nitrogen atmosphere After 2 hours, thesolvent was evaporated under vacuum. ¹H NMR (400 MHz, DMSO-d₆) δ 9.53(s, 1H), 7.73-7.67 (m, 2H), 7.62-7.54 (m, 1H), 7.35 (dt, J=10.40, 2.56Hz, 1H), 7.27 (t, J=8.35 Hz, 2H), 7.19 (dt, J=8.60, 2.44 Hz, 1H), 5.72(s, 1H), 5.50 (s, 2H); ES MS m/z 455.9836 (M+H calcd for C₁₉H₁₁BrF₄NO₃,requires 455.9859).

Example 468

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(1H)-one

In a 50 ml round bottom flask5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde(0.456 gm, 1.0 mmol) was stirred in dichloromethane (5 mL). To thismixture was added a 2M THF solution of dimethyl amine (1.25 ml, 2.5mmol). The mixture was allowed to stir under nitrogen atmosphere and atroom temperature for 2 hours. To this mixture was then added triacetoxysodium borohydride (0.37 g, 1.75 mmol) followed by two to three drops ofacetic acid. The mixture was then stirred at rt overnight. The solventswere then removed by evaporation and the residue was taken up in ethylacetate (30 ml) and washed with aqueous sodium bicarbonate and brine.The organics were then combined, dried over MgSO₄, and concentrated invacuo. The crude product was purified by flash column chromatographyusing a solvent gradient of (3:1) ethyl acetate-hexane to (0:100) ethylacetate to give 0.14 g (30% yield) of the desired product. ¹H NMR (300MHz, DMSO-d₆) δ 7.73-7.58 (m, 2H), 7.42 7.30 (m, 3H), 7.22 (dt, J=8.73,2.60 Hz, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.04 (s, 2H), 1.96 (s, 6H);ES-MS m/z 485.0 (M+H). ES-HRMS m/z 485.0457 (M+H calcd forC₂₁H₁₈BrF₄N₂O₂, requires 485.0489).

Example 469

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(morpholin-4-ylmethyl)pyridin-2(1H)-one

The title compound was prepared by reacting5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde(0.456 g, 1 mmol) with morpholine (0.13 ml, 1.5 mmol) and triacetoxysodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (7 mL) by usinga similar procedure to the one described for Example 468. The crudeproduct was purified by flash column chromatography. Elution with(50:50→0:100) hexanes-ethyl acetate to give 0.15 g (29% yield) of thedesired product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.57 (m, 2H),7.43-7.31 (m, 3H), 7.20 (dt, J=8.64, 2.48 Hz, 2H), 6.85 (s, 1H), 5.44(s, 2H), 3.37 (app t, J=4.37 Hz, 4H), 3.13 (s, 2H), 2.08 (t, J=4.19 Hz,4H); ES-HRMS m/z 527.0600 (M+H calcd for C₂₃H₂₀BrF₄N₂O₃ requires527.0594).

Example 470

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-{[(2-methoxyethyl)amino]methyl}pyridin-2(1H)-one

The title compound was prepared by reacting5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde-(0.319g, 0.7 mmol) with 2-methoxy ethylamine (0.086 ml, 1.0 mmol) andtriacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (4mL)by using a procedure, similar to the one described for Example 468.The crude product was purified by flash column chromatography. Elutionwith (50:50→100) hexanes-ethyl acetate to give 0.13 g of the desiredproduct.

¹H NMR (400 MHz, CDCl₃) δ 7.54 (q, J=6.89 Hz, 1H), 7.41-7.33 (m, 1H),7.19 (s, 1H), 6.99 (t, J=7.90 Hz, 2H), 6.90 (dt, J=7.90, 2.78, Hz, 1H),6.80 (dt, J=10.60, 2.34 Hz, 1H), 6.51 (s, 1H), 5.24 (s, 2H), 3.33 (t,J=4.69 Hz, 1H), 3.30 (s, 3H), 2.57 (t, J=4.86 Hz, 2H), 1.53 (s, 2H);ES-HRMS m/z 515.0548 (M+H calcd for C₂₂H₂₀BrF₄N₂O₃, requires 515.0594).

Example 471

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid

In a 100 ml round bottom flask,3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one(1.70 g, 3.7 mmol) was dissolved in acetone (10 mL) and cooled to 0° C.in ice bath. To the reaction was added 1M acetone solution of Jones (5ml, excess amount). Additional Jones reagent was added over time(approximately 6 hours) until the reaction was complete. The reactionwas then concentrated down to dryness. The residue was then taken up inethyl acetate (10 mL) and washed with brine. The dark yellow to browncolored crude product was purified by dissolving in 1N aqueous NaOH. Theremaining organic impurities were removed by extracting with diethylether. The organic layers were discarded and the aqueous layer wasacidified with dilute HCl (til _(p)H app 1) to precipitate the pure acidwhich was then filtered and triturated with ether to obtain 1.17 g (65%)of the desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (q, J=9.41 Hz,1H), 7.57-7.50 (m, 1H), 7.34 (dt, J=10.11, 2.78 Hz, 1H), 7.28-7.23 (m,3H), 7.18 (dt, 8.90, 2.42 Hz, 1H), 5.47 (s, 2H). ES-HRMS m/z 471.9814(M+H calcd for C₁₉H₁₁BrF₄NO₄, requires 471.9808)

Example 472

Methyl4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-methylbenzoateStep 1: Preparation of methyl4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoate

In a 50 ml one neck round bottom flask equipped with a stir bar, DeanStark trap, and condenser 4-amino-2-methyl-methylbenzoate (1.19 g, 11.63mmol) and 4-hydroxy-6-methyl-2H-pyran-2-one (1.611 g, 12.78 mmol) weremixed together and dissolved in 1,2-dichlorobenzene (5 mL). The mixturewas vigorously stirred and then placed in a preheated oil bath at 165 0°C. The reaction was maintained at 165 0° C. for 1.5 hour and cooled toroom temperature. The reaction was worked up by diluting with toluene(10 mL) and then stirring at room temperature for 2 hours. A light brownprecipitate resulted. The crude product was isolated by filtration andthen triturated with ether. ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H),7.93 (s, 1H), 7.85 (dd, 8.46 Hz, 1H), 7.26 (d, J=8.12 Hz, 1H), 5.91 (d,J=2.32 Hz, 1H), 5.54 (d, J=2.32 Hz, 1H), 3.84 (s, 3H), 1.99 (s, 3H),1.73 (s, 3H). ES-HRMS m/z 272.0880 (M−H calcd for C₁₅H₁₄NO₄, requires272.1001).

Step 3: Preparation of Methyl4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoate

Methyl4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoatewas prepared by reacting—methyl4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoate withN-bomosuccinamide in acetonitrile by following a procedure, similar tothe one described in Example 465-step 3. ¹H NMR (400 MHz, DMSO-d₆) δ7.95 (s, 1H), 7.87 (dd, J=7.76, 2.02 Hz, 1H), 7.31 (d, J=8.54, 1H), 6.09(s, 1H), 3.85 (s, 3H), 1.99 (s, 3H), 1.74 (s, 1H). ES-HRMS m/z 352.0195(M+H calcd for C₁₅H₁₄BrNO₄, requires 352.0185)

Step 4: The title compound was prepared by taking methyl4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoate(0.92 g, 2.61 mmol) and dissolving in dry DMF (5 mL). Potassiumcarbonate (0.432 g, 3.13 mmol) and 2,4 Difluuorobenzyl bromide (0.335ml, 2.61 mmol) were then added. The mixture was allowed to stir at roomtemperature for 2 hours.

The reaction was then worked up by pouring it into 100 ml of ice-waterwhich resulted in a precipitate forming which was isolated by filteringthrough a fritted funnel. The crude product was washed with ether anddried in vacuum to give 0.85 g (76.20%) of pure product. ¹H NMR (400MHz, DMSO-d₆) δ 7.98 (d, J=1.6 Hz, 1H), 7.88 (dd, J=8.04, 2.0 Hz, 1H),7.69 (q, J=8.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.17 (dt, J=8.7, 2.3 Hz, 1H),6.71 (s, 1H), 5.32 (s, 2H), 3.86 (s, 3H), 2.00 (s, 3H), 1.86 (s, 3H).ES-HRMS m/z 478.0459 (M+H calcd for C₂₂H₁₉BrF₂NO₄ requires 478.0466).

Examples 473-476

The compounds of Examples 473-476 are prepared by derivitazion of thecompounds of Example 472.

M + H Compound No. R MF Requires ESHRMS m/z Ex. 473 -CO₂H C₂₁H₁₆BrF₂NO₄464.0310 464.0324 Ex. 474 -CH₂OH C₂₁H₁₈BrF₂NO₃ 450.0500 450.0517 Ex. 475C(O)NH(CH₂)₂OCH₃ C₂₄H₂₂BrF₂N₂O₄ 521.0888 521.0865 Ex. 476 C(O)NHCH₃C₂₂H₂₀BrF₂N₂O₃ 477.0626 477.0609

NMR characterization of compounds of Examples 473-476

NMR characterization of compounds of Examples 473-476 Ex. No. NMR Data473 ¹H-NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 7.95 (d, J = 1.70 Hz,1H), 7.86 (dd, J = 7.88, 1.91 Hz, 1H), 7.67 (dq, J = 8.47, 1.89 Hz, 1H),7.36 − 7.30 (m, 2H), 7.17 (dt, J = 8.54, 2.48 Hz, 1H), 6.71 (s, 1H),5.32 (s, 2H), 1.99 (s, 3H), 1.87 (s, 3H) 474 ¹H NMR (400 MHz, DMSO-d₆) δ7.67 (q, J = 8.5 Hz, 1H), 7.34 (dd, J = 10.04, 2.77 Hz, 1H), 7.32 (s,1H), 7.24 (dd, J = 8.39, 1.47 Hz, 1H), 7.17 (dt, J = 8.84, 2.6 Hz, 1H),7.08 (d, J = 7.94 Hz, 1 H), 6.66 (s, 1H), 5.30 (s, 2H), 5.25 (t, J =6.01 Hz, 1H), 4.5 (d, J = 6.68 Hz, 2H), 1.91 (s, 3H ), 1.86 (s,3H) 475¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (app t, J = 5.4 Hz, 1H), 7.84 (s, 1H),7.76 (dd, J = 8.06, 1.63 Hz, 1H), 7.68 (dq, J = 8.77, 2.04 Hz, 1H), 7.33(dt, J = 9.76, 2.03 Hz, 1H), 7.27 (d, J = 8.34 Hz, 1H), 7.17 (ddt, J =8.51, 2.63, 0.91 Hz, 1H), 6.70 (s, 1H), 5.31 (s, 2H), 4.50 (t, J = 5.6Hz , 1H), 3.47 − 3.36 (m, 4H), 3.24 (s, 3H), 1.97 (s, 3H), 1.87 (s, 3H)476 ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 − 8.49 (m, 1H), 7.82 (s, 1H), 7.74(dd, J = 8.22, 1.79 Hz,1H), 7.69 (q, J = 6.75 Hz, 1H), 7.33 (dt, J =9.88, 2.57 Hz, 1H), 7.26(d, J = 8.52 Hz, 1H), 7.17 (dt, J = 8.93, 2.16Hz, 1H), 6.69 (s, 1H), 5.31 (s, 2H), 2.77 (d, J = 4.58 Hz, 3H), 1.97 (s,3H), 1.86 (s, 3H)

Example 477

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-oneStep 1—Preparation of−1-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one

The title compound was prepared in a similar manner to the procedureoutlined above for4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-methylbenzoate. ¹H NMR(400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.59 (d, J=2.84 Hz, 1H), 7.45 (dd,J=8.39, 2.44 Hz, 1H), 7.06 (d, J=7.44, 1H), 5.89 (d, J=2.73 Hz, 1H),5.53 (d, J=2.30, 1H), 1.91 (s, 3H), 1.75 (s, 3H). ES-HRMS m/z 294.0127(M+H calcd for C₁₃H₁₃BrNO₃, requires 294.0130).

Step 2—Preparation of−1-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

1-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (7.35 g,25.0 mmol) was dissolved in DMF (15 mL) and stirred with potassiumcarbonate (4.14 g, 30.0 mmol) and 2,4 difluorobenzyl bromide (3.21 ml(25.0 mmol) at room temperature for 2 hours. The reaction was worked upby pouring in to 300 ml ice water under continuous stirring. A whiteprecipitate was obtained which was isolated by filtering and furtherpurified by triturating with ether to give 3.06 g (29%) of the desiredproduct. ¹H NMR (400 MHz, DMSO-d₆) δ 7.65-7.59 (m, 2H), 7.49 (dd,J=8.45, 2.22 Hz, 1H), 7.31 (dt, J=9.79, 2.22 Hz, 1H), 7.16-7.08 (m, 2H),6.05 (d, J=2.58 Hz, 1H), 5.93 (d, J=2.66 Hz, 1H), 5.08 (s, 2H), 1.93 (s,3H), 1.77 (s, 3H). ES-HRMS m/z 420.0390 (M+H calcd for C₂₀H₁₇BrF₂NO₂,requires 420.0411).

Step 3: Preparation of4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one

In a 50 ml round bottom flask previously evacuated and filled withnitrogen,1-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(0.420 g, 1.0 mmol) was dissolved in dry THF (10 mL). To this mixturewas added Pd (PPh₃)₄ (0.173 g, 0.15 mmol). The reaction flask was sealedwith a rubber septum, evacuated and filled with nitrogen. Under anitrogen atmosphere, tributyl(vinyl)tin (0.35 ml, 1.2 mmol) was added tothe sealed reaction mixture and stirred overnight at 50° C.

The reaction was worked up by quenching with water and extraction of theproduct with ethyl acetate. The crude product was purified by columnchromatography. Elution with ethyl acetate-hexanes (50:50→(0:100) gave0.32 g (69%) of the desired product.

Step 4: The title compound was prepared by reacting4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one(0.64 g, 1.74 mmol) with N-bromosuccinamide (0.325 g, 1.83 mmol) inacetonitrile (9 mL) at 0° C. using a similar procedure as described instep 3 of Example 465, to give 0.423 g (54.5% after recrystallization)of the desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (app q, J=7.59Hz, 1H), 7.48 (s, 1H), 7.42 (dd, J=8.21, 1.98 Hz, 1H), 7.33 (dt,J=10.00, 2.27 Hz, 1H), 7.17 (dt, J=8.51, 2.44 Hz, 1H), 7.13 (d, J=7.88Hz, 1H) 6.74 (dd, J=11.29, 6.34 Hz, 1H), 6.67 (s, 1H), 5.88 (d, J=17.85,1H), 5.32-5.30 (m, 2H), 1.92 (s, 3H), 1.88 (s, 3H). ES-HRMS m/z 446.0579(M+H calcd for C₂₂H₁₉BrF₂NO₂, requires 446.0568).

Example 478

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1,2-dihydroxyethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one(0.126 g, 0.28 mmol) was dissolved in a mixture of acetone (3 mL) andwater (1 mL). To this was added 4-methylmorpholine N-oxide (0.032 g,0.28 mmol) and catalytic amount (approximately 5 mgs) of osmiumtetroxide was added, and stirred under nitrogen atmosphere. Afterapproximately 2 hours, the reaction was worked up by evaporation of theacetone. The product was extracted into ethyl acetate and concentratedto give a dark colored solid which was further purified by columnchromatography to give 0.049 g (37% yield)of charcoal colored solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.67 (q, J=8.24 Hz, 1H), 7.37-7.23 (m, 3H),7.17 (dt, J=8.62, 2.62 Hz, 1H), 7.07 (dd, J=9.36, 2.24 Hz, 1H), 6.65 (s,1H), 5.30 (s, 2H), 4.74 (t, J=6.16 Hz, 1H), 4.57-4.50 (m, 1H), 3.45 (appt, J=6.12 Hz, 2H), 3.41-3.37 (m, 1H), 1.91 (s, 3H), 1.85 (s, 3H).ES-HRMS m/z 480.0625 (M+H calcd for C₂₂H₂₁BrF₂NO₄, requires 480.0623).

Example 479

methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate Step 1:Preparation of methyl4-chloro-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

A condensation reaction with methyl 3-amino-4-chlorobenzoate (14.5 g,78.2 mmol) and 4-hydroxy-6-methyl pyranone under reaction conditionsimilar to the one described in Example 465-step 3 gave 12.32 (53.8%) ofdesired product.

Step-3—Preparation ofmethyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

In a 250 ml round bottom flask, methyl4-chloro-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate (5.28 g,18.0 mmol) from step 1 was reacted with 2,4-difluoro-benzylbromide (3.72g, 18.0 mmol) in DMF using similar procedure as in Example 472 step 3.After aqueous work up and chromatographic purification, 2.3 g (30%) pureproduct was obtained.

Step 4: methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoatewas prepared by reactingmethyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(2.3 g, 5.47 mmol) with N-bromosuccinamide (0.97 g, 5.47 mmol) inacetonitrile (10 mL) at 0° C., using a similar procedure as described instep 3 of Example 465, to give 1.80 g (66.2%) of the desired product. ¹HNMR (400 MHz, DMSO-d₆) δ 8.06-8.03 (m, 2H), 7.86 (d, J=9.70 Hz, 1H),7.68 (q, J=7.62, 1H), 7.34 (dt, J=10.07, 2.46 Hz, 1H), 7.17 (dt, J=8.72,2.90 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H).ES-MS m/z 495.9757 (M−H calcd for C₂₁H₁₄BrClF₂NO₄, requires 495.9795).

Example 480

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoicacid

In a 50 ml round bottom flask,methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(0.450 g, 0.90 mmol) was stirred in THF (5 mL) To this mixture was addedNaOH (0.120 g, 3.0 mmol) as a solution in water (1.5 mL). The reactionmixture was stirred at room temperature overnight. The THF wasevaporated and the residue was acidified with dilute HCl. A whiteprecipitate was obtained. The product was filtered, washed with waterand dried in vacuum to give 0.375 g (86% yield) of the desired product.¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (dd, J=7.78, 1.73 Hz, 1H), 7.71-7.65(m, 2H), 7.53 (d, J=9.08 Hz, 1H), 7.33 (dt, J=9.95, 2.59 Hz, 1H), 7.17(dt, J=8.22, 2.59 Hz, 1H), 6.68 (5, 1H), 5.32 (s, 2H), 1.89 (s, 3H).ES-MS m/z 481.9585 (M−H calcd for C₂₀H₁₂BrClF₂NO₄, requires 481 9601).

Example 481

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-hydroxy-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) and 3-Amino4-methylbenzyl alcohol (25.0 g, 182.2 mmol) were taken up in 25 ml of1,2-dichlorobenzene. The solution was heated to 165° C. in a 250 mlround bottom flask equipped with a J-Kem temperature controller probe,and a heating mantle. In a separate 250 ml round bottom flask4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) was suspended in 25 mlof 1,2-dichlorobenzene and also heated to 165° C. The pyrone solutionwas poured into the flask containing the aniline and the reactionstirred at 165° C. for 20 minutes. The reaction was allowed to cool toroom temperature. Reaction contents were washed with saturated NaHCO₃(aq.). Separated the organic and aqueous layers. Aqueous layer was madeacidic with dropwise addition of concentrated HCl. The product wasextracted from the acidic aqueous layer with n-BuOH. N-BuOH removed invacuo to produce a reddish brown oil. (8.5 g, 19%). Contents carriedforward to next reaction with no further purification. ¹H NMR (300 MHz,CD₃OD) δ 7.35 (m, 2H), 7.08 (s, 1H), 6.08 (br s, 1H), 5.81 (br s, 1H),4.60 (s, 2H), 2.01 (s, 3H), 1.87 (s, 3H). LC/MS, t_(r)=1.42 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254nm, at 50° C.). ES-MS m/z 246.1131 (M+H). ES-HRMS m/z 246.1107 (M+Hcalcd for C₁₄H₁₆NO₃ requires 246.1125).

Step 2:4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(1H)-one

4-hydroxy-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one (from Step 1) (8.0 g, 32.6 mmol) was stirred brisklyat room temperature with 2,4-difluorobenzyl bromide (4.2 ml, 32.6 mmol)and K₂CO₃ (4.5 g, 32.6 mmol) in 50 ml of dimethylformamide. Afterstirring for 8 hours, H₂O (100 ml) was added to reaction mixture. Theproduct was extracted with ethyl acetate. Ethyl acetate layer wasseparated and dried over Na₂SO₄. Ethyl acetate was removed in vacuo. Ayellow oil was obtained. The oil was passed through a plug of silica gelfirst eluting with 500 ml of ethyl acetate/hexane (1:1) This eluent wasset aside. Next, ethyl acetate (100%) was passed through the plug untildesired product was completely flushed from silica (3 liters). Solventwas removed in vacuo. Light yellow oil obtained (7.5 g, 62%). ¹H NMR(300 MHz, CD₃OD) δ 7.60 (app q, J=6.44 Hz, 1H), 7.42 (d, J=0.81 Hz, 2H),7.15 (s, 1H) 7.06 (m, 2H), 6.21 (dd, J=1.61, 1.00 Hz, 1H), 6.12 (d,J=2.62 Hz, 1H), 5.16 (s, 2H), 4.65 (s, 2H), 2.07 (s, 3H), 1.93 (s, 3H);LC/MS, t_(r)=2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 372 (M+H).

Step 3: Preparation of the title compound.4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(1H)-one(from Step 2) (4.0 g, 10.8 mmol) was stirred at room temperature withN-bromosuccinimide (2.1 g, 11.9 mmol) in 100 ml of CH₂Cl₂ for 2.0 hours.The reaction was evaporated on a rotary evaporator and the resultingsolid was washed with acetonitrile and dried in vacuo to yield a whitesolid (3.9 g, 80%). ¹H NMR (300 MHz, CDCl₃) δ 7.67 (app q, J=6.24 Hz,1H), 7.35 (d, J=1.01 Hz, 2H), 7.10 (s, 1H), 7.04 (m, 1H), 6.91 (ddd,J=11.08, 8.66, 2.42 Hz, 1H), 6.15 (d, J=0.63 Hz, 2H), 5.29 (s, 2H), 4.66(s, 2H), 2.08 (s, 3H), 1.97 (s, 3H); ES-MS m/z 450 (M+H). ES-HRMS m/z450.0467 (M+H calcd for C₂₁H₁₉BrF₂NO₃ requires 450.0511).

Example 482

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

The title compound was prepared by a procedure similar to the onedescribed for Example 481, except that the product from Step 2, Example481 was chlorinated instead of being brominated. The procedure is asfollows:4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one(from Step 2, Example 481 above) (7.0 g, 18.8 mmol) was refluxed withN-chlorosuccinimide (2.5 g, 18.8 mmol) in 50 ml of CH₂Cl₂ overnight. Thereaction was evaporated on a rotary evaporator and the resulting solidwas stirred in MeOH. The precipitate was collected on a filter pad,washed with MeOH and dried in vacuo to yield a white solid (1.6 g, 21%).¹H NMR (300 MHz, DMF-d₇) δ 7.85 (app q, J=6.44 Hz, 1H), 7.43 (d, J=0.81,1H), 7.42-7.23 (m, 3H), 6.84 (s, 1H), 5.48 (s, 2H), 4.67 (s, 2H), 2.05(s, 3H), 2.03 (s, 3H); ES-MS m/z 406 (M+H). ES-HRMS m/z 406.1033 (M+Hcalcd for C₂₁H₁₆ClF₂NO₄ requires 406.1016).

Example 483

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-oneStep 1: Preparation of 3-amino-4-chloro-benzyl alcohol

3-Nitro-4-chloro-benzyl alcohol (23.0 g, 122.6 mmol) is taken up inisopropyl alcohol (175 ml) and water (35 ml). Iron powder (<10 micron)(68.0 g, 1.2 moles) and NH₄Cl (66.0 g, 1.2 moles) are added. Thesuspension is stirred overhead at 70° C. in a three neck round bottomflask equipped with a heating mantle and a J-Kem temperature controllerprobe. After 4 hours, isopropyl alcohol was removed in vacuo. Water (100ml) and concentrated HCl (10 ml) was added to mixture. Contents aretransferred to a separtory funnel and ethyl acetate is used to extractthe aqueous layer of impurities. The aqueous layer was then basifiedwith 50% aqueous NaOH. The product was extracted from the basic aqueouslayer with ethyl acetate. The ethyl acetate layer was dried over Na₂SO₄and then removed in vacuo. The remaining residue was taken up in 50%ethyl acetate/hexane and the precipitate was collected on a filter pad.Precipitate was washed with 50% ethyl acetate/hexane to yield aflocculent brown solid (8.4 g, 44%). ¹H NMR (300 MHz, CD₃OD) δ 7.17 (d,J=8.26 Hz, 1H), 6.86 (d, J=2.01 Hz, 1H), 6.66 (dd, J=2.01, 0.61 Hz, 1H),4.51 (s, 2H); LC/MS, t_(r)=0.32 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.); ES-MS m/z158 (M+H).

Step 2:1-[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one

3-amino-4-chloro-benzyl alcohol (8.0 g, 51.0 mmol) and4-hydroxy-6-methyl-2-pyrone (6.4 g, 51.0 mmol) were taken up in1,2-dichlorobenzene (50 ml). The mixture was plunged into a 165° C. oilbath where it stirred for 20 minutes. The reaction was cooled to roomtemperature and the reaction was worked up by washing with saturatedNaHCO₃ (aq.) and extracting impurities with ethyl acetate. The productremained in the aqueous layer. The basic aqueous layer was made acidicwith concentrated HCl. The product was extracted from the acidic aqueouslayer with ethyl acetate. The ethyl acetate layer was dried over Na₂SO₄and the solvent removed in vacuo. The product was obtained as a yellowoil in a 26% yield and was carried through to the next step with nofurther purification. ¹H NMR (300 MHz, CD₃OD) δ 7.62 (d, J=8.26 Hz, 2H),7.51 (dd, J=8.46, 2.22 Hz, 1H), 7.36 (d, J=2.01 Hz, 1H), 6.13 (br s,1H), 5.84 (d, J=2.42 Hz, 1H), 4.68 (s, 2H), 1.97 (s, 3H); LC/MS,t_(r)=0.25 minutes and 1.41 minutes (tautomer), (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 266 (M+H).

Step 3:1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

1-[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one(from step 2) (3.5 g, 13.2 mmol) was taken up in DMF (10 ml) and cooledto 0° C. 2,4-Difluorobenzyl bromide (1.7 ml, 13.2 mmol) and K₂CO₃ (1.8g, 13.2 mmol) were added and the reaction stirred for 6 hours. Thereaction was worked up by adding saturated NaHCO₃ (aq.) and extractingwith ethyl acetate. The ethyl acetate extraction was washed with water,and the aqueous layer was extracted with ethyl acetate. The organiclayers were combined and dried over Na₂SO₄, filtered, and the solventremoved in vacuo. The product was obtained in 83% crude yield andcarried through to the next step as a brown oil. LC/MS, t_(r)=2.48minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 392 (M+H). ES-HRMS m/z 392.0853(M+H calcd for C₂₀H₁₇ClF₂NO₃ requires 392.0860).

Step 4: The title compound was prepared from1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(from step 3) (1.8 g, 4.6 mmol) and N-bromosuccinimide (0.82 g, 4.6mmol) by dissolving them in CH₂Cl₂ (10 ml) and stirring for 2 hours atroom temperature. The solvent was removed in vacuo and the residue wastaken up in CH₃CN. The precipitate was collected on a filter pad andrinsed with CH₃CN to yield a white solid (370 mg, 17%). ¹H NMR (300 MHz,CDCl₃) δ 7.65 (app q, J=6.24 Hz, 1H), 7.52 (d, J=8.26 Hz, 1H), 7.40 (dd,J=826, 2.01 Hz 1H), 7.26 (d, J=0.81 Hz, 1H), 7.03 (m, 1H), 6.91 (ddd,J=11.08, 8.66, 2.42 Hz, 1H), 6.17 (d, J=0.81 1H), 5.29 (s, 2H), 4.63 (s,2H), 2.02 (s, 3H); ES-MS m/z 471 (M+H). ES-HRMS m/z 471.9953 (M+H calcdfor C₂₀HC₆BrClF₂NO₃ requires 471.9944).

Example 484

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

The title compound was prepared from1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(2.4 g, 6.1 mmol) and NCS (815.0 mg, 6.1 mmol) in 65° C. dichloroethane(20 ml). A catalytic amount of dichloroacetic acid (2 drops) was added.After two hours the solvent was removed in vacuo and the residue wastaken up in diethyl ether. The precipitate was collected on a filter padand then taken up in 50% ethyl acetate/hexanes to remove residualsuccinimide. The precipitate was collected on a filter pad and thendried in vacuo to produce a white powder (180 mg, 6.9%). ¹H NMR (300MHz, CDCl₃) δ 7.61 (app q, J=6.44 Hz, 1H), 7.52 (d, J=8.26 Hz, 1H), 7.40(dd, J=8.26, 2.01 Hz 1H), 7.27 (d, J=2.01 Hz, 1H), 7.00 (m, 1H), 6.91(m, 1H), 6.20 (s, 1H), 5-29 (s, 2H), 4.65 (s, 2H), 2.03 (s, 3H); ES-MSm/z 426 (M+H). ES-HRMS m/z 426.0453 (M+H calcd for C₂₀H₁₆Cl₂F₂NO₃requires 426.0470).

Example 485

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-onehydrochloride Step 1: Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzaldehyde

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one(1.5 g, 3.33 mmol) was dissolved in 75% CH₃CN/CH₂Cl₂ (20 ml) and cooledto 0° C. Dess-Martin Periodinane (2.8 g, 6.66 mmol) was added and thereaction stirred for four hours. At this time, the reaction was quenchedwith 5% sodium bisulfite (aq.). The product was extracted with ethylacetate. The combined organic extracts were then washed with saturatedNaHCO₃ (aq.). The aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated. The resulting residue was taken up in diethyl ether andthe precipitate was collected on a filter pad and washed with morediethyl ether to yield a white solid (1.35 g, 91%). ¹H NMR (300 MHz,CDCl₃) δ 10.00 (s, 1H), 7.91 (dd, J=7.65, 1.61 Hz, 1H), 7.65 (m, 2H),7.57 (d, J=7.85 Hz, 1H), 7.03 (m, 1H), 6.95 (ddd, J=12.69, 8.86, 2.62Hz, 1H), 6.19 (s, 1H), 5.31 (s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MSm/z 448 (M+H). ES-HRMS m/z 448.0347 (M+H calcd for C₂₁H₁₇BrF₂NO₃requires 448.0354).

Step 2: Preparation of the title compound.3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzaldehyde(from step 1) (0.50 g, 1.11 mmol) was dissolved in CH₂Cl₂ (10 ml).N,N-dimethylamine (2.0 M in THF) (1.11 ml, 2.22 mmol) was added. Thismixture stirred for at room temperature for 12 hours. Next, sodiumtri-acetoxyborohydride (0.47 g, 2.22 mmol) was added and the reactionstirred for two more hours. The reaction was washed with 1 N NaOH (aq.)and then extracted with CH₂Cl₂. The combined organic extracts werewashed with water. The aqueous layer was separated and extracted withCH₂Cl₂. The combined organic extracts were dried over Na₂SO₄, filteredand concentrated in vacuo. The resulting residue was taken up in diethylether. 1M HCl in diethyl ether (5 ml) was added and the precipitate wascollected on a filter pad. This precipitate was hygroscopic. Thehygroscopic solid was then taken up in hot ethyl acetate. Hexane wasadded until a precipitate crashed out. The precipitate was collected ona filter pad to yield a white solid (150 mg, 26%). ¹H NMR (400 MHz, D₂O)6, 7.42 (m, 3H), 7.17 (s, 1H), 6.86 (m, 2H), 6.53 (s, 1H), 5.20 (s, 2H),4.18 (s, 1H), 2.72 (s, 6H), 1.85 (s, 3H), 1.82 (s, 3H); ES-MS m/z 477(M+H). ES-HRMS m/z 477.0955 (M+H calcd for C₂₃H₂₄BrF₂N₂O₂ requires477.0984).

Example 4863-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{5-[(isopropylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H)-onehydrochloride

The title compound was prepared by reductive amination of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzaldehyde(from step 1) (0.50 g, 1.11 mmol) with iso-propyl amine (0.13 g, 2.22)according to the procedure described above for Example 485 (Step 2) togive the desired compound (0.49 g, 84%) ¹H NMR (400 MHz, CD₃OD) δ 7.64(app quartet, J=6.58 Hz, 1H), 7.53 (m, 2H), 7.29 (br s, 1H), 7.03 (m,1H), 6.68 (s, 1H), 5.36 (s, 2H), 4.22 (s, 2H), 3.46 (m, 1H), 2.06 (s,3H), 2.01 (s, 3H), 1.37 (d, J=6.58 Hz, 6H); ES-MS m/z 491 (M+H). ES-HRMSm/z 491.1107 (M+H calcd for C₂₄H₂₆BrF₂N₂O₂ requires 491.1140).

Example 487

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide

Step 1: Preparation of methyl3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate

4-Hydroxy-6-methyl-2-pyrone (22.9 g, 181.6 mmol) andmethyl-3-amino-2-methylbenzoate (25 g, 151.3 mmol) were suspended in 50ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flaskequipped with a J-Kem temperature controller probe, a Dean-Stark trap,and a heating mantle. The reaction was heated to 165° C. for 15 minutes,during which, water and some 1,2-dichlorobenzene was collected in theDean Stark trap. The reaction was allowed to cool to about 110° C. Atthis point, 200 ml of toluene was added. The flask was plunged into a 0°C. ice bath while stirring. “Oiling out” occurred. Perhaps too muchtoluene was added so some of the solvent was removed in vacuo. The oilwent back into solution and a light brown precipitate remained. Thetoluene mixture was allowed to stir for 72 hours at room temperature. Aprecipitate was collected on a filter pad. The precipitate was filteredand washed 3 Limes with toluene, 3 times with 50° C. water to removeexcess pyrone, and dried in vacuo to give a tan solid (16.5 g, 40%yield). ¹H NMR (300 MHz, CD₃OD) δ 8.06 (dd, J=8.06, 1.61 Hz, 1H), 7.80(d, J=1.61 Hz, 1H), 7.56 (d, J=3.06, Hz, 1H), 6.15 (dd, J=2.42, 0.81 Hz,1H), 5.86 (d, J=2.42 1H), 3.94 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H);ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1066 (M+H calcd for C₁₅H₁₆NO₄requires 274.1074).

Step 2: Preparation of methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4methylbenzoate

Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate(from Step 1) (16.5 g, 60.4 mmol) 2,4-difluorobenzyl bromide (7.8 ml,60.4 mmol) were taken up in 250 ml of N,N-dimethylformamide and themixture was cooled to 0° C. K₂CO₃ (8.3 g, 60.4 mmol) was added andreaction stirred for 12 hours during which time the reaction was allowedto warm to room temperature. LC/MS indicated the presence of startingmaterial after 12 hours. An excess of K₂CO₃ was added at roomtemperature along with 0.50 ml of 2,4-difluorobenzyl bromide. Thereaction stirred for an additional two hours. Saturated NaHCO₃ (aq.) waspoured into reaction vessel. The solution was extracted with ethylacetate and the organic layers were combined then washed with water. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The organic layers were combined and dried over Na₂SO₄,and evaporated. The product was carried on to the next step as a crudeoil (24.1 g, quantitative yield). ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd,J=7.85, 1.61 Hz, 1H), 7.82 (d, J=1.61, 1H), 7.52 7.44 (m, 2H), 7.01-6.88(m, 2H), 6.05 (d, J=2.62 Hz, 1H), 5.97 (dd, J=2.62, 0.81 Hz, 1H), 5.08(s, 2H), 3.93 (s, 3H), 2.20 (s, 3H), 1.89 (s, 3H); ES-MS m/z 400 (M+H).ES-HRMS m/z 400.1374 (M+H calcd for C₂₂H₂₀F₂NO₄ requires 400.1355).

Step 3: Preparation of3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4methylbenzoate (14 g, 35.0 mmol) (from step 2) was taken up in THF (25ml) and H₂O. 2.5 N NaOH (aq.) was added and the reaction stirred for 30minutes at room temperature. The reaction was made acidic via theaddition of concentrated HCl. The product was extracted with ethylacetate. The ethyl acetate extraction was dried over Na₂SO₄, filtered,and the solvent removed in vacuo. Upon vacuum removal of the solvent,the product crashed out of the ethyl acetate. This precipitate wascollected on a filter pad and washed with a 50 ethyl acetate/hexanes toyield a white powder (9 g, 7%). ¹H NMR (300 MHz, CDCl₃) δ 8.01 (dd, J=,1.61 Hz, 1H), 7.84 (d, J=1.61 Hz, 1H), 7.52-7.47 (app q, J=8.26, 1H),7.43 (d, J=8.06 Hz, 1H), 7.00-6.88 (m, 2H), 6.19 (d, J=2.62 Hz, 1H),6.05 (dd, J=2.62, 1.81 Hz, 1H), 5.17 (s, 2H), 2.19 (s, 3H), 1.90 (s,3H); ES-HR/MS m/z 386.12 (M+H calcd for C₂₁H₁₈F₂NO₄ requires 386.1198).

Step 4: Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (5.9 g, 15.2 mmol) (from step 3 above) was taken up indichloromethane (25 ml). N-Bromosuccinimide was added and the reactionstirred for 14 hours. The dichloromethane was removed in vacuo and theresidue was taken up in acetonitrile. The precipitate was collected on afilter pad and rinsed with acetonitrile to yield the desired product asa white solid (5.2 g, 74%). ¹H NMR (300 MHz, CD₃OD) δ 7.87 (dd, J=7.85,1.61,Hz, 1H), 7.82 (d, J=1.81 Hz, 1H), 7.69 (app q, J=8.06 Hz 1H), 7.57(d, J=8.06 Hz, 1H), 7.09 (dt, J=8.66, 2.22 Hz, 1H), 6.70 (s, 1H), 5.40(s, 2H), 2.14 (s, 3H), 2.02 (s, 3H); ES MS m/z 464 (M+H). ES-HRMS m/z464.0275 (M+H calcd for C₂₁H₁₇BrF₂NO₄ requires 464.0304).

Step 5: Preparation of the title compound.3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (from Step 4 above) (1.9 g, 4.10 mmol) was dissolved in 20 ml ofCH₂Cl₂. Ethanolamine (297 μl, 4.92 mmol) was added, followed, in order,by EDCI (0.764 g, 4.92 mmol), 1-hydroxybenzotriazole (0.6659, 4.92 mmol)and triethylamine (1.14 ml, 8.20 mmol). The reaction was stirred at roomtemperature overnight. The reaction was quenched with NH₄Cl andextracted 3 times with ethyl acetate. The combined organic layer wasthen washed with saturated NaHCO₃ (aq.) and extracted 3 times with ethylacetate. The organic layers were combined and washed with H₂O andextracted 3 times with ethyl acetate. The organic layers were combinedand dried over Na₂SO₄ and evaporated. The resulting residue wastriturated with diethyl ether/hexane to obtain a solid, which was driedin vacuo to give a white solid (15 g, 72%). ¹H NMR (300 MHz, CDCl₃) δ7.93 (dd, J=7.85, 1.61 Hz, 1H), 7.65 (d, J=1.61 Hz, 1H), 7.62 (app q,J=8.26 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.39-7.30 (m, 1H), 7.03-6.97(m, 1H), 6.88-6.81 (m, 1H), 6.25 (s, 1H), 5.20 (s, 2H), 3.70-3.52 (m,1H), 3.16-3.12 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H); ES-MS m/z 507 (M+H).ES-HRMS m/z 507.0719 (M+H calcd for C₂₃H₂₂BrF₂N₂O₄ requires 507.0726).

Examples 488-491

The compounds of Examples 488-491-476 are prepared essentially accordingto the procedures set forth for Example 487.

Compound % M + H ESHRMS No. R Yield MF Requires m/z Ex. 488—NH(CH₂)₂OCH₃ 84 C₂₄H₂₄BrF₂N₂O₄ 528.0882 521.0868 Ex. 489 —NHCH₃ 79C₂₂H₂₀BrF₂N₂O₃ 477.0620 477.0602 Ex. 490 —N(CH₃)₂ 54 C₂₃H₂₂BrF₂N₂O₃491.0776 491.0753 Ex. 491 -morpholine 65 C₂₅H₂₄BrF₂N₂O₄ 533.0858533.0882

Example 492

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1-hydroxy-1-methylethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-oneStep 1: Preparation of methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

Methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate(as prepared above) (1.8 g, 4.51 mmol) was taken up in CH₂Cl₂ (10 ml).N-bromosuccinimide (0.80 g, 4.51 mmol) was added and the mixture stirredat room temperature for two hours. The CH₂Cl₂ is removed in vacuo andthe residue is taken up in CH₃CN. The resulting precipitate is collectedon a filter pad and washed with CH₃CN to yield a white solid (0.30 g,14%, first crop) ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J=8.06, 1.61 Hz,1H), 7.80 (d, J=1.61 Hz, 2H), 7.65 (app q, J=8.46 Hz, 1H), 7.48 (d,J=8.06, 1H), 7.05-6.99 (m, 1H), 6.96-6.89 (m, 1H), 6.16 (s, 1H), 5.31(s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.96 (s, 3H). ES-HRMS m/z 478.0476(M+H calcd for C₂₂H₁₉BrF₂NO₄ requires 478.0476).

Step 2: Preparation of the title compound. Methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl2-oxopyridin-1(2H)-yl]-4-methylbenzoate (0.22 g, 0.46 mmol) was taken upin THF and cooled to 0° C. MeMgCl (3.0 M in THF) (0.73 ml, 2.2 mmol) wasslowly added to the 0° C. solution. The reaction was allowed to proceedwithout maintaining the 0° C. bath temperature. The reaction wascomplete within two hours. At this time the mixture was quenched withsaturated NH₄Cl (aq.) and extracted with ethyl acetate. The organiclayers were combined, washed with H₂O, and extracted with ethyl acetate.The organic layers were combined and dried over Na₂SO₄, filtered, andevaporated. The residue was taken up in 50% ethyl acetate/hexanes. Theprecipitate was collected on a filter pad and washed with 50% ethylacetate/hexanes to yield a white solid (0.10 g, 45%). ¹H NMR (300 MHz,CD₃OD) δ 7.70 (app q, J=8.26, Hz, 1H), 7.54 (dd, J=8.06, 2.01 Hz, 1H),7.40 (d, J=1.81 Hz, 1H), 7.12-7.06 (m, 2H), 6.68 (s, 1H), 5.40 (s, 2H),2.05 (s, 3H), 2.02 (s, 3H), 1.57 (s, 6H). ES-HRMS m/z 478.0785 (M+Hcalcd for C₂₃H₂₃BrF₂NO₃ requires 478.0824).

Example 493

methyl3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

The title compound was prepared by taking up methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate(1.46 g, 3.66 mmol) in dichloroethane (25 ml) and addingN-chlorosuccinimide (0.49 g, 3.66 mmol), dichloroacetic acid(catalytic), and heating to 50° C. for 6 hours. At this time, thesolvent was removed in vacuo and the residue taken up in diethyl ether.The precipitate was collected on a filter pad. ¹H NMR (300 MHz, CDCl₃) δ8.07 (dd, J=7.85, 1.61 Hz, 11), 7 80 (d, J=1.81 Hz, 2H), 7.62 (app q,J=846 Hz, 1H), 7.48 (d, J=7.85, 1H), 7.05-6.95 (m, 1H), 6.93-6 89 (m,1H), 6.19 (s, 1H), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.97 (s,3H). ES-HRMS m/z 434.0932 (M+H calcd for C₂₂H₁₉ClF₂NO₄ requires434.0965).

Example 494

methyl4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoateStep 1: Preparation of methyl3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

4-Hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) andmethyl-3-amino-2-chlorobenzoate (30 g, 161.6 mmol) were suspended in 75ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flaskequipped with a J-Kem temperature controller probe, a Dean Stark trap,and a heating mantle. The reaction was heated to 175° C. for 20 minutes,during which, water and some 1,2-dichlorobenzene was collected in theDean-Stark trap. The reaction was allowed to cool to about 110° C. Atthis point, 200 ml of toluene was added. The toluene mixture was allowedto stir for 72 hours at room temperature. A precipitate was collected ona filter pad. The precipitate was filtered and washed 3 times withtoluene, 3 times with 50° C. water to remove excess pyrone, and dried invacuo to give a tan solid (13.0 g, 27% yield). ¹H NMR (300 MHz, CD₃OD) δ8.26 (d, J=1.81 Hz, 1H), 8.14 (dd, J=8.26, 1.81 Hz, 1H), 7.54 (d,J=8.26, Hz, 1H), 6.14 (dd, J=2.42, 1.0 Hz, 1H), 5.83 (d, J=2.42 1H),4.00 (s, 3H), 1.96 (s, 3H); LC/MS, t_(r)=1.81 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 294 (M+H).

Step 2: Preparation of methyl3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl 3-chloro-4-(4-hydroxy-6-methyl 2-oxopyridin-1(2H)-yl)benzoate(from Step 1) (2.4 g, 8.17 mmol) was taken up in DMF (10 ml).2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K₂CO₃ (1.13 g, 8.17mmol) were added. The reaction stirred for 6 hours at room temperature.At this time, the reaction was poured into water (200 ml) and extractedwith ethyl acetate. The ethyl acetate layer was dried over Na₂SO₄,filtered, and the solvent removed in vacuo to give amber oil (2.62 g,77% crude yield). LC/MS, t_(r)=2.79 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z294 (M+H).

Step 3: Preparation of the title compound. Methyl3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(from step 2) (2.60 g, 6.21 mmol) was taken up in CH₂Cl₂ (20 ml).N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture stirredat room temperature for 4 hours. The CH₂Cl₂ is removed in vacuo and theresidue is taken up in CH₃CN. The resulting precipitate is collected ona filter pad and washed with CH₃CN to yield a white solid (0.75 g, 24%).¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=1.88 Hz, 1H), 8.06 (dd, J=8.19,1.75 Hz, 13H), 7.59 (app q, J=8.46 Hz, 1H), 7.33 (d, J=8.19, 1H), 6.96(dt, J=8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s,2H), 3.95 (s, 3H), 1.95 (s, 3H). ES-HRMS m/z 497.9892 (M+H calcd forC₂₂H₁₆BrClF₂NO₄ requires 497.9914).

Example 495

3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-oneStep 1 Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with 4-benzyloxy-2(1H)-pyridinone (20 g, 99.6 mmol) andN,N-dimethyl formamide (50 mL). K₂CO₃ (13.7 g, 99.6 mmol) and KI (1.6 g,9.6 mmol) were added followed by 3-fluorobenzyl bromide (14.6 mL, 119.4mmol). The reaction mixture was heated for 18 h at 80 C. The reactionmixture was concentrated in vacuo and treated with hot ethyl acetate.The solids were filtered off, the filtrate was poured into water and wasextracted with ethyl acetate. The organic extract was washed with brine,dried with anhydrous Na₂SO₄, and concentrated in vacuo. The residue wasdissolved in hot ethyl acetate and precipitated with hexanes to give thetitle compound (10 g, 33%). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J=8.4 Hz,1H), 7.37 (m, 5H), 7.07 (d, J=8.4 Hz, 1H), 7.01 (app d, J=8.4 Hz, 2H),6.17 (d, J=2.68 and 7.6 Hz, 1H), 6.04 (d, J=2.68 Hz, 1H), 5.10 (s, 2H),5.08 (s, 2H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −114.88 (1F) ppm. ES-HRMSm/z 310.1271 (M+H calcd for C₁₉H₁₇FNO₂ requires 310.1238).

Step 2 Preparation of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one

A small Parr bottle was charged with SC-82484 (10 g, 32.3 mmol), ethanol(175 mL) and 10% Pd/C (0.5 g). The system was flushed twice with bothnitrogen and hydrogen. The reaction mixture was hydrogenated at 30 psiuntil no starting material was visible by LC-MS. The reaction mixturewas slurried with Celite and then was filtered through a pad of celite.The filtrate and ensuing ethanol washes were concentrated in vacuo togive a beige solid. ¹H NMR (400 MHz, CD₃OD) δ 7.53 (d, J=7.67 Hz, 1H),7.32 (m, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.05 (dd,J=2.58 and 7.67 Hz, 1H), 5.83 (d, J=2.0 Hz, 2H), 5.10 (s, 2H) ppm. ¹⁹FNMR (400 MHz, CD₃OD) δ-115.33 (1F) ppm. ES-HRMS m/z 218.0641 (M+H calcdfor C₁₂H₁₁FNO₂ requires 218.0612).

Step 3 Preparation of4-[(2,4-difluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one

The product from Step 2 (0.5 g, 2.28 mmol) and 2,4-difluoro benzylamine(4 mL, 33.6 mmol) were combined in a nitrogen flushed culture tube. Thetube was capped and heated at 180 C for 24 h. The excess amine wasdistilled in vacuo and the residue was chromatographed on silica (95:5ethyl acetate:methanol). The final compound was isolated as a lightyellow solid (0.16 g, 36%). ¹H NMR (400 MHz, CD₃OD) δ 7.33 (m, 3H), 7.03(d, J=8 Hz, 1H), 6.96 (m, 3H), 6.95 (m, 1H), 5.97 (dd, J=3.2 and 8.0 Hz,1H), 5.48 (d, J=2.56 Hz, 1H), 5.02 (s, 2H), 4.33 (s, 2H) ppm. ¹⁹F NMR(400 MHz, CD₃OD) δ −113.88 (1F), −115.33 (1F), −116.78 (1F) ppm. ES-HRMSm/z 345.1221 (M+H calcd for C₁₉H₁₇F₃N₂O requires 345.1209).

Step 4 Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one

N-Bromo succinimide (81 mg, 0.46 mmol) was added to a solution of theproduct from Step 3 (0.15 g, 0.44 mmol) in methylene chloride (10 mL).After stirring at 25 C for 1 h, the reaction was complete by LC-MS. Thereaction mixture was poured into saturated aqueous NaHCO₃. The aqueousmixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous MgSO₄, and concentrated in vacuo. ¹HNMR (400 MHz, CDCl₃) δ 7.3-7.2 (m, 4H), 7.07 (app t, J=7.6 Hz, 2H), 6.97(m, 2H), 6.80 (m, 2H), 5.78 (d, J=7.6 Hz, 1H), 5.30 (br s, 1H), 5.08 (s,2H), 4.46 (d, J=6 Hz, 2H) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −110.64 (1F),−112.75 (1F), −114.79 (1F) ppm. ES-HRMS m/z 423.0275 (M+H calcd forC₁₉H₁₅BrF₃N₂O requires 423.0314).

Example 496

3-bromo-1-(3-fluorobenzyl)-4-{[3-(trifluoromethyl)benzyl]amino}pyridin-2(1H)-one

The title compound was prepared essentially as in Example 495. ¹H NMR(400 MHz, CDCl₃) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.27 (q, J=3.1, 9.0 Hz,1H), 6.96 (app t, J=8.8 Hz, 2H), 5.71 (d, J=7.6 Hz, 1H), 5.4 (br m, 1H),5.08 (s, 2H), 4.52 (d, J=5.6 Hz, 2H) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −63(3F), −112 (1F) ppm. ES-HRMS m/z 455.0388 (M+H calcd for C₂₀H₁₆BrF₄N₂Orequires 455.0377).

Example 497

3-bromo-1-(3-fluorobenzyl)-4-{[4-fluoro-2-(trifluoromethyl)benzyl]amino}pyridin-2(1H)-one

The title compound was prepared essentially as in Example 495. ¹H NMR(400 MHz, CDCl₃) δ 7.43 (m, 2H), 7.27 (m, 3H), 7.07 (m, 2H), 6.99 (m,2H), 5.65 (d, J=10 Hz, 1H), 5.46 (br s, 1H), 5.09 (s, 2H), 4.64 (s, 2H)ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −61.31 (3F), −112.69 (1F), 112.97 (1F)ppm. ES-HRMS m/z 473.0246 (M+H calcd for C₂₀H₁₅BrF₅N₂O requires473.0282).

Example 498

Preparation of-bromo-4-[(4-chloro-2-fluorobenzyl)amino]-1-(3-fluorobenzyl)pyridin-2(1H)-one

The title compound was prepared essentially as in Example 495. ¹H NMR(400 MHz, CDCl₃) δ 7.27 (m, 1H), 7.19 (app t, J=8.8 Hz, 1H), 7.10 (m,4H), 6.95 (app t, J=8.8 Hz, 2H), 5.74 (d, J=8 Hz, 1H), 5.40 (br s, 1H),5.08 (s, 2H), 4.47 (d J=6 Hz, 2H) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ−112.67 (1F), −116.39 (1F) ppm. ES-HRMS m/z 439.0047 (M+H calcd forC₁₉H₁₅ClBrF₂N₂O requires 439.0019).

Example 499

The title compound was prepared essentially as in Example 495. ¹H NMR(400 MHz, CDCl₃) δ 7.35-7.2 (m, 1H), 7.27 (dd, J=2.5 and 8 Hz, 1H), 7.05(app d, J=7.2 Hz, 3H), 6.97 (m, 4H), 5.72 (d, J=7.6 Hz, 1H), 5.41 (br s,1H), 5.08 (s, 2H), 4.46 (d, J=6.4 Hz, 2H) ppm. ¹⁹F NMR (400 MHz, CDCl₃)δ −112.5 (1F), −113 (1F) ppm. ES-HRMS m/z 405.0431 (M+H calcd forC₁₉H₁₆BrF₂N₂O requires 405.0409).

Example 500

Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-oneStep 1 Preparation of4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one

(0.3 g, 1.39 mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) werecombined in a nitrogen flushed culture tube. The tube was capped andheated at 180 C for 24 h. The excess amine was distilled in vacuo. ¹HNMR (400 MHz, CD₃OD) δ 8.44 (dd, J=1.7 and 4.8 Hz, 2H), 7.38 (q, J=10and 15 Hz, 1H), 7.14 (d, J=4.8 Hz, 2H), 6.95 (m, 2H), 5.90 (dd, J=1 and2.5 Hz, 1H), 5.47 (d, J=2, 1H), 5.28 (s, 2H), 4.33 (s, 2H), 2.27 (s, 3H)ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −113.73 (1F), −116.66 (1F) ppm. ES-HRMSm/z 342.1422 (M+H calcd for C₁₉H₁₈F₂N₃O requires 342.1418).

Step 2 Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one

N-Bromo succinimide (77 mg, 0.43 mmol) was added to a solution of theproduct of Step 1-(0.14 g, 0.41 mmol) in methylene chloride (10 mL).After stirring at 25 C for 1 h, the reaction was complete by LC-MS. Thereaction mixture was poured into saturated aqueous NaHCO₃. The aqueousmixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was triturated with hexanes to give the titlecompound as a yellow solid (81 mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ 8.47(dd, J=1.6 and 4.8 Hz, 2H), 7.24 (q, J=6.4 and 13.6 Hz, 1H), 7.01 (d,J=6.4 Hz, 2H), 6.83 (m, 2H), 5.68 (s, 1H), 5.25 (s, 2H), 4.45 (d, J=6.4Hz, 2H), 2.12 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CDCl₃) δ −110.51 (m, 1F),−114.66 (m, 1F) ppm. ES-HRMS m/z 420.0524 (M+H calcd for C₁₉H₁₇BrF₂N₃Orequires 420.0523).

Example 501

Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one

The title compound was prepared essentially as in Example 500.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.8 Hz, 2H), 7.55 (app t, J=6 Hz,1H), 7.21 (m, 2H), 6.83 (m, 2H), 5.65 (s, 1H), 5.34 (d, J=5.2 Hz, 1H),5.27 (s, 2H), 4.45 (s, 2H), 2.10 (d, J=4.8 Hz, 3H) ppm. ¹⁹F NMR (400MHz, CDCl₃) δ −110.74 (1F), −114.86 (1F) ppm. ES-HRMS m/z 420.0533 (M+Hcalcd for C₁₉H₁₇BrF₂N₃O requires 420.0523).

Example 502

Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-oneStep 1 Preparation of4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one

1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.3 g, 1.26mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) were combined in anitrogen flushed culture tube. The tube was capped and heated at 180 Cfor 24 h. The excess amine was distilled in vacuo and the residue waschromatographed on silica (1:1 hexanes:ethyl acetate). The compound wasapproximately 50% pure and was carried on without further purification(0.633 g). ¹H NMR (400 MHz, CD₃OD) δ 7.53 (m, 1H), 7.41 (m, 1H), 7.16(t, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.00 (s, 1H), 5.42 (s, 1H), 5.42 (s,1H), 4.37 (s, 2H), 1.93 (s, 3H) ppm. LC/MS, t_(r)=4.65 minutes (5 to 95%acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 363 (M+H).

Step 2 Preparation of3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one

N-Bromo succinimide (168 mg, 0.945 mmol) was added to a solution of theproduct of Step 1-(0.633 g) in methylene chloride (10 mL). Afterstirring at 25 C for 1 h, the reaction was 50% complete by LC-MS.Additional N-bromo succinimide (150 mg) was added and the reaction wasstirred at 25 C for 12 h. The reaction mixture was poured into saturatedaqueous NaHCO₃. The aqueous mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried with anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified by reverse phasechromatography (60:40 Acetonitrile: water with 0.05% trifluoroaceticacid). The title compound was isolated as the TFA salt (0.161 g, 23%).¹H NMR (400 MHz, CD₃OD) δ 7.53 (m, 1H), 7.35 (q, J=8, 15.6 Hz, 1H), 7.16(t, J=8 Hz, 2H), 6.96 (app q, J=8, 16.4 Hz, 2H), 6.12 (s, 1H), 4.86 (s,2H), 1.94 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −77.33 (1F), −113.60(1F), −116.63 (1F), −121.50 (1F) ppm. ES-HRMS m/z 441.0231 (M+H calcdfor C₁₉H₁₄BrF₄N₂O requires 441.0220).

Example 503

Preparation of3-chloro-4-[(2,4-difluorobenzyl)amino]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one

1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.3 g, 1.26mmol) and 2,4-difluoro benzylamine (1 mL, 84 mmol) were combined in annitrogen flushed culture tube. The tube was capped and heated at 180 Cfor 24 h. The excess amine was distilled in vacuo and the residue wasused without further purification. N-Chloro succinimide (168 mg, 1.26mmol) was added to a solution of the residue in methylene chloride (10mL). After stirring at 25 C for 1 h, the reaction mixture was pouredinto saturated aqueous NaHCO₃. The aqueous mixture was extracted withethyl acetate. The organic layer was washed with brine, dried withanhydrous Na₂SO₄, and concentrated in vacuo. The residue waschromatographed on silica (25:75 hexanes:ethyl acetate) to give thetitle compound (32 mg, 6%). ¹H NMR (400 MHz, CD₃OD) δ 7.55 (m, 1H), 7.36(q, J=9.2 and 15.2 Hz, 1H), 7.18 (t, J=7.6 Hz, 2H), 6.98 (m, 2H), 6.15(s, 1H), 4.62 (s, 2H), 1.96 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ−113.78 (1F), −116.72 (1F), −121.57 (1F) ppm. ES-HRMS m/z 397.0752 (M+Hcalcd for C₁₉H₁₄ClF₄N₂O requires 397.0725).

Example 504

Preparation of3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrileStep 1 Preparation of 3-phthalimidomethyl-benzonitrile

3-Phthalimidomethyl-benzonitrile was prepared as described in theliterature (Bookser, B. C.; Bruice, T. C. J. Am. Chem. Soc. 1991, 113,4208-18.)

Step 2 Preparation of 3-(aminomethyl)benzonitrile

3-(Aminomethyl)benzonitrile was prepared as described in the literature.(Bookser, B. C.; Bruice, T. C. J. Am. Chem. Soc. 1991, 113, 4208-18.)

Step 3 Preparation of3-[(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)methyl]benzonitrile

A nitrogen flushed pyrex reaction tube was charged with3-(aminomethyl)benzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-methyl-2-pyrone(1 g, 7.9 mmol) and water (20 mL). The tube was capped and was heated toreflux. After 1.5 h, the product precipitated from solution. Thereaction mixture was cooled to room temperature, filtered and washedwith water. The product was used without further purification (1.67 g,88%) ¹H NMR (400 MHz, dmso-d₆) δ 10.53 (s, 1H), 7.61 (d, J=8 Hz, 1H),7.52 (t, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 5.79 (dd, J=1 and 2.5 Hz,1H), 5.56 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 2.14 (s, 3H) ppm. ES-HRMS m/z241.0968 (M+H calcd for C₁₄H₁₃N₂O₂ requires 241.0972).

Step 5 Preparation of3-{[4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The product from Step 4 (0.5 g, 2.08 mmol) and 2,4-difluoro benzylamine(2 mL, 16.8 mmol) were combined in a nitrogen flushed culture tube. Thetube was capped and heated at 180 C for 24 h. The excess amine wasdistilled in vacuo and the residue was triturated with ethylacetate/hexanes to precipitate the starting materials. The residue waschromatographed on reverse phase (1:1 water:acetonitrile with 0.05%trifluoroacetic acid). The product of Step 5 was isolated as a whitesemi-solid (0.125 g, 15%). ¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=8 Hz,1H), 7.49 (t, J=8 Hz, 1H), 7.41 (m, 3H), 6.94 (m, 2H), 5.89 (dd, J=0.8and 2.7 Hz, 1H), 5.47 (d, J=2.8 Hz, 1H), 5.27 (s, 2H), 4.34 (s, 2H),2.18 (s, 3H) ppm. LC/MS, t_(r)=4.87 minutes (5 to 95% acetonitrile/waterover 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z366 (M+H).

Step 6 Preparation of3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

N-Chloro succinimide (36 mg, 0.27 mmol) was added to a solution of theproduct of Step 5 (0.125 g, 0.26 mmol) in methylene chloride (10 mL).After stirring at 25 C for 2 h, the reaction was complete by LC-MS. Thereaction mixture was poured into saturated aqueous NaHCO₃. The aqueousmixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was triturated with acetonitrile to give the title compound as atan solid (20 mg, 13%). ¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, J=8.4 Hz,1H), 7.49 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.33 (q, J=8.4 and 14.8 Hz,1H), 6.94 (m, 2H), 6.00 (s, 1H), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s,3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −114.00 (1F), −116.89 (1F) ppm.LC/MS, t_(r)=5.49 minutes (5 to 95% acetonitrile/water over 8 minutes at1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 400 (M+H).

Example 505

Preparation of4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzonitrile

The title compound was prepared essentially as in Example 504. ¹H NMR(400 MHz, CD₃OD) δ 7.66 (d, J=8 Hz, 2H), 7.33 (q, J=8 and 15.2 Hz, 1H),7.25 (d, J=8 Hz, 2H), 6.94 (m, 2H), 6.01 (s, 1H), 5.36 (s, 2H), 4.55 (s,2H), 2.19 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −77.52 (1F), −113.89(1F), −116.71 (1F) ppm. LC/MS, t_(r)=5.49 minutes (5 to 95%acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 400 (M+H).

Example 506

Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-oneStep 1 Preparation of (3-amino-4-fluorophenyl)methanol

A flask equipped with overhead stirrer was charged with4-fluoro-3-nitrobenzyl alcohol (20 g, 0.117 mol) and 200 mL of 5:1isopropanol:water. Ammonium chloride (62 g, 1.17 mol) was added followedby iron filings (65 g, 1.17 mol). The mixture was stirred at 70 C for1.5H when it was shown to be complete by LC-MS. The liquid was decantedand the solids were washed with additional isopropanol: water. Theisopropanol was removed and the residue was diluted with 0.5 N HCl andwas extracted with ethyl acetate. The aqueous layer was brought to pH12-14 with 2.5 N NaOH and was extracted with ethyl acetate. The organiclayer was dried with anhydrous Na₂SO₄ and concentrated in vacuo.3-Amino-4-fluorophenyl methanol was isolated as a brown solid (4.5 g,27%) and was used without further purification. LC/MS, t_(r)=2.40minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 142 (M+H). ES-HRMS m/z 142.0692(M+H calcd for C₇H₈FNO requires 142.0663).

Step 2 Preparation of1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one

A 100 mL round bottomed flask equipped with stirbar, Dean-Stark trap andreflux condenser was charged with (3-amino-4-fluorophenyl)methanol (4.5g, 31.9 mmol), 4-hydroxy-6-methyl-2-pyrone (4 g, 31.9 mmol) ando-dichlorobenzene (5 mL). The system was immersed in a 170 C oil bathfor 10 minutes. The solvent was removed in vacuo and the residue waschromatographed on reverse phase (75:25 water:acetonitrile with 0.05%TFA). The product contained some starting materials after purificationand was used without further purification (1.27 g, 15%). ¹H NMR (400MHz, dmso-d₆) δ 7.39 (m, 1H), 7.20 (dd, J=2.2 and 7.6 Hz, 1H), 6.74 (dd,J=2.7 and 9.6 Hz, 1H), 5.93 (dd, J=1.2 and 2.2 Hz, 1H), 5.22 (dd, J=0.4and 2.2 Hz, 1H), 2.12 (s, 3H) ppm. ES-HRMS m/z 250.0862 (M+H calcd forC₁₃H₁₃FNO₃ requires 250.0874).

Step 3 Preparation of4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one

A 100 mL roundbottomed flask (nitrogen purged) was charged with1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one(1.2 g, 4.82 mmol) and N,N-dimethyl formamide (10 mL). Potassiumcarbonate (0.6 g, 4.4 mmol) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4mmol) was added and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with saturated aqueousNaHCO₃ and extracted with ethyl acetate. The organic layer wasconcentrated in vacuo and the residue was chromatographed on silica (9:1methylene chloride: ethanol). The impure oil (0.3 g, 17%) was carried onwithout further purification. ¹H NMR (400 MHz, CD₃OD) δ 7.54 (m, 2H),7.30 (m, 2H), 7.02 (m, 2H), 6.17 (dd, J=1 and 2.8 Hz, 1H), 6.03 (d,j=2.8 Hz, 1H), 5.14 (s, 2H), 4.62 (s, 2H), 2.14 (s, 3H) ppm. ¹⁹F NMR(400 MHz, CD₃OD) δ −111.35 (1F), −115.97 (1F), −127.31 (1F) ppm. LC/MS,t_(r)=5.05 minutes (5 to 95% acetonitrile/water over 8 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 375 (M+H).

Step 4 Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one

N-Bromo succinimide (50 mg, 0.3 mmol) was added to a solution of theproduct of Step 3 (0.12 g, 0.32 mmol) in N,N dimethyl formamide (4 mL).After stirring at 25 C for 2 h, trifluoroacetic acid (50 μL) was added.After 1 h, additional N-Bromo succinimide (30 mg) was added. After 1 h,the reaction was complete by LC-MS. The reaction mixture was poured intobrine and was extracted with ethyl acetate. The organic layer was washedwith brine, dried with anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was chromatographed on reverse phase (95:5 methylene chloride:ethanol). The title compound was isolated as the TFA salt (38 mg, 26%).¹H NMR (400 MHz, CD₃OD) δ 7.64 (q, J=7.6 and 14.8 Hz, 1H), 7.51 (m, 1H),7.31 (app t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.34(s, 2H), 4.62 (s, 2H), 2.06 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ−111.48 (1F), −115.92 (1F), 127.23 (1F) ppm. ES-HRMS m/z 454.0228 (M+Hcalcd for C₂₀H₁₆BrF₃NO₃ requires 454.0260).

Example 507

Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid Step 1 Preparation of methyl 4-fluoro-3-nitrobenzoate

A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet,stirbar, addition funnel and thermocouple was charged with4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and methanol (300 mL). Thesystem was cooled to 0 C and acetyl chloride (27 mL, 0.37 mol) was addeddropwise. The system was warmed to room temperature, the addition funnelwas replaced with a reflux condenser, and was heated to reflux for 1.5h. The reaction mixture was cooled to room temperature, quenched withsaturated aqueous NaHCO₃, and extracted with ethyl acetate. The organicextract was washed with brine, dried with Na₂SO₄ and concentrated invacuo to give methyl 4-fluoro-3 nitrobenzoate as an orange solid (40.6g, 75%). ¹H NMR (400 MHz, CD₃OD) δ 8.67 ((dd, J=2.2 and 6.8 Hz, 1H),8.34 (dddd, J=2.2, 4.4, 6.4 and 8.8 Hz, 1H), 7.55 (dd, J=8.8 and 10.8Hz, 1H), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M+H calcd for C₈H₇FNO₄requires 200.0354).

Step 2 Preparation of methyl 3-amino-4-fluorobenzoate

A Parr bottle was charged with the product of Step 1-(40 g, 0.2 mol),ethanol (400 mL) and 10% Pd/C (1 gg). The system was flushed twice withnitrogen and hydrogen. The reaction mixture was hydrogenated at 40 psiuntil no starting material was visible by LC-MS. The reaction mixturewas slurried with Celite and then was filtered through a pad of celite.The filtrate and ensuing ethanol washes were concentrated in vacuo togive methyl 3-amino-4-fluorobenzoate as an orange solid (30.6 g, 91%).¹H NMR (400 MHz, CD₃OD) δ 7.54 (d, J=8.7 Hz, 1H), 7.35 (m, 1H), 7.06 (t,J=8.7 Hz, 1H), 3.09 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −131.02 (1F)ppm. ES-HRMS m/z 199.0281 (M+H calcd for C₈H₇FNO₄ requires 199.02).

Step 3 Preparation of methyl4-fluoro-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

A 250 mL round bottomed flask equipped with stirbar, Dean-Stark trap andreflux condenser was charged with the product of Step 3 (30 g, 0.18mol), 4-hydroxy-6-methyl-2-pyrone (22.6 g, 0.18 mol), ando-dichlorobenzene (90 mL). The system was immersed in a 170 C oil bathfor 30 minutes and was then cooled to room temperature. The reactionmixture was washed with aqueous Na₂CO₃ (38 g, 0.36 mol, 300 mL water).The aqueous layer was washed with ethyl acetate and then was acidifiedto pH 1-2 with concentrated HCl. This was extracted with ethyl acetate,which was then dried with MgSO₄ and concentrated in vacuo. The viscousorange oil was used without further purification (14.4 g, 28%). ¹H NMR(400 MHz, CD₃OD) δ 8.18 (dddd, J=2.3, 5.2, 7.2 and 8.8 Hz, 1H), 7.97(dd, J=2 and 7.2 Hz, 1H), 7.44 (t, J=8.8 Hz, 1H), 6.09 (d, J=1.8 Hz,1H), 5.78 (d, J=2.4 Hz, 1H), 3.9 (s, 3H), 2.14 (s, 3H) ppm. ¹⁹F NMR (400MHz, CD₃OD) δ −117.29 (1F) ppm. ES-HRMS m/z 278.0796 (M+H calcd forC₁₄H₁₃FNO₄ requires 278.0823).

Step 4 Preparation of methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 3 (14.4 g, 51.9 mmol) andN,N-dimethyl formamide (40 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL,72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, waspoured into saturated aqueous NaHCO₃ and was extracted with ethylacetate. The organic layer was washed with brine, dried with Na₂SO₄ andconcentrated in vacuo to give the title product, as an orange oil(21.59), which was carried on to the next reaction without furtherpurification. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (dddd, J=2.2, 4.8, 7.2 and8.8 Hz, 1H), 8.00 (dd, J=2.2 and 7.2 Hz, 1H), 7.56 (td, J=2.4, 6.4 and9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J=0.8 and2.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98(s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.34 (1F), −116.00 (1F),−117.35 (1F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C₂₁H₁₇F₃NO₄requires 404.1104).

Step 5 Preparation of methyl3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate

A 250 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 4 (21 g, 52 mmol) andN-methyl-2-pyrrolidine (100 mL). N-Chloro succinimide (8.3 g, 62 mmol)was added and the reaction mixture was stirred at 65 C for 2 h. Themixture was then cooled to room temperature, poured into saturatedaqueous NaHCO₃ and extracted with ethyl acetate. The organic layer waswashed with brine, dried with Na₂SO₄, and concentrated in vacuo. Theresidue was triturated with diethyl ether and filtered to give the titlecompound, as a white powder (5.9 g, 25%). ¹H NMR (400 MHz, CD₃OD) δ 8.22(dddd, J=2, 4.8, 6.8 and 8.8 Hz, 1H), 8.03 (dd, J=2 and 7.2 Hz, 1H),7.62 (q, J=8.4 and 14.8 Hz, 1H), 7.48 (t, J=14 Hz, 1H), 7.04 (m, 2H),6.69 (s, 1H), 5.36 (s, 2H), 3.91 (s, 3H), 2.08 (s, 3H) ppm. ¹⁹F NMR (400MHz, CD₃OD) δ −111.38 (1F), −115.97 (1F), −117.43 (1F) ppm. ES-HRMS m/z438.0723 (M+H calcd for C₂₁H₁₆ClF₃NO₄ requires 438.0714).

Step 6 Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid

A 100 mL round bottomed flask was charged with the product of Step 5(2.5 g, 5.72 mmol), tetrahydrofuran (40 mL), methanol (10 mL), and water(10 mL). To this slurry was added 2.5 N NaOH (4.6 mL, 11.4 mmol). Thereaction mixture became clear after 5 minutes and the reaction wascomplete in 35 minutes by LC-MS. The organics were removed on the rotaryevaporator and the remaining solution was acidified to pH 3 with 6N HCl.The desired compound was precipitated by the addition of diethyl etherand subsequent filtration. The title compound was isolated as a whitepowder (2.5 g, 98%). ¹H NMR (400 MHz, dmso-d₆) δ 8.10 (dddd, J=2.1, 4.8,7.2 and 8.4 Hz, 1H), 8.00 (dd, J=2.1 and 7.6 Hz, 1H), 7.66 (q, J=9.2 and15.6 Hz, 1H), 7.57 (t, J=8.8 Hz, 1H), 7.34 (td, J=2.4 and 10.4 Hz, 1H),7.17 (tdd, J=1, 2.7 and 8.4 Hz, 1H), 6.76 (s, 1H), 5.33 (s, 2H), 1.98(s, 3H) ppm. ¹⁹F NMR (400 MHz, dmso-d₆) δ −109.32 (1F), −113.64 (1F),−117.22 (1F) ppm. ES-HRMS m/z 424.0575 (M+H calcd for C₂₀H₁₄ClF₃NO₄requires 424.0558).

Example 508

Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-methylbenzamide

To a reaction vessel (borosilicate culture tube) was added3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (0.300 g, 0.708 mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45mmol). N,N-Dimethylformamide (3 mL) was added to the reaction vesselfollowed by approximately 1.2 g of the polymer bound carbodiimide resin(1.38 mmol/9). Additional N,N-dimethylformamide (2 mL) was then added tothe reaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was thenadded to the reaction vessel and the reaction apparatus was orbitallyshaken at room temperature overnight. At this time the reaction wasdiluted with tetrahydrofuran (20 mL) and treated with approximately 2.17g of polyamine resin (2.63 mmol/g) and approximately 2.8 g ofmethylisocyanate functionalized polystyrene (1.5 mmol/g) and the orbitalshaking was continued at 200 RPM at room temperature for 3 hours. Thereaction vessel was then opened and the solution phase product wasseparated from the insoluble quenched byproducts by filtration andcollection into a vial. After partially evaporation the insolublebyproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate wasevaporated by blowing N₂ over the vial and the resulting solid wastriturated with diethyl ether to give an off-white solid. (0.168 g, 59%)

¹H NMR (400 MHz, CD₃OD) δ 8.02 (dddd, J=2, 4.4, 7.2 and 8.4 Hz, 1H),7.80 (dd, J=2 and 6.8 Hz, 1H), 7.62 (q, J=8 and 14.4 Hz, 1H), 7.34 (t,J=8.8 Hz, 1H), 7.04 (m, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 3.29 (s, 3H),1.98 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −108.94 (1F), −113.55 (1F),−117.76 (1F) ppm. ES-HRMS m/z 437.0861 (M+H calcd for C₂₁H₁₇ClF₃N₂O₃requires 437.0874).

Examples 509-518

By following the method of Example 508 and replacing N-methylamine withthe appropriate amine, the compounds of Examples 509-518 are prepared.

Example % M + H ESHRMS No. R₁ R₂ Yield MF Requires m/z Ex. 509 CH₃ CH₃59 C₂₂H₁₉ClF₃N₂O₃ 451.1031 451.1016 Ex. 510 H CH₂CH₂OH 70 C₂₂H₁₉ClF₃N₂O₄467.0980 467.0985 Ex. 511 CH₂CH₂N(CH₃)— CH₂CH₂N(CH₃) 70 C₂₅H₂₄ClF₃N₃O₃506.1453 506.1447 Ex. 512 CH₂CH₂O— CH₂CH₂O— 19 C₂₄H₂₁ClF₃N₂O₄ 493.1101493.1136 Ex. 513 H CH₂CH₂OCH₃ 59 C₂₃H₂₁ClF₃N₂O₄ 481.1136 481.1136 Ex.514 CH₃ CH₂CH₂OH 63 C₂₃H₂₁ClF₃N₂O₄ 481.1136 481.1131 Ex. 515 HCH₂CH₂CH₂OH 51 C₂₃H₂₁ClF₃N₂O₄ 481.1136 481.1121 Ex. 516 H CH₂CH(OH)CH₂OH64 C₂₃H₂₁ClF₃N₂O₅ 497.1086 497.1102 Ex. 517 H C(CH₃)₂CH₂OH— 54C₂₄H₂₃ClF₃N₂O₄ 495.1293 495.1303 Ex. 518 CH₂CH₂NH— CH₂CH₂NH— 34C₂₃H₂₂ClF₃N₃O₃ 491.89

Example 519

Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid

Step 1 Preparation of methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate(7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL). N-Bromo succinimide(3.5 g, 19.8 mmol) was added and the reaction mixture was stirred atroom temperature for 30 minutes. The mixture poured into saturatedaqueous NaHCO₃ and extracted with ethyl acetate. The organic layer waswashed with brine, dried with Na₂SO₄, and concentrated in vacuo. Theresidue was triturated with diethyl ether and filtered to give the titlecompound as a white powder (3.49 g). ¹H NMR (400 MHz, CD₃OD) δ 8.16 (qd,J=3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J=2.12 Hz, 1H), 7.64 (q, J=8.4 and14.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.04 (m, 2H), 6.60 (s, 1H), 5.34(s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ−111.51 (1F), −115.98 (1F), −117.43 (1F) ppm. ES-HRMS m/z 494.0387 (M+Hcalcd for C₂₂H₁₉BrF₂NOs requires 494.0409).

Step 2 Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid

A 100 mL round bottomed flask was charged with the product of Step 2(3.4 g, 7.05 mmol), tetrahydrofuran (40 mL), methanol (10 mL), and water(10 mL). To this slurry was added 2.5 N NaOH (5.6 mL, 14.1 mmol). Thereaction mixture became clear after 5 minutes and the reaction wascomplete in 1 h by LC MS. The organics were removed on the rotaryevaporator and the remaining solution was acidified to pH 1-2 with 6NHCl. The desired compound was precipitated by the addition of water anddiethyl ether and subsequent filtration. The title compound was isolatedas a white powder (2.64 g, 80%) ¹H NMR (400 MHz, CD₃OD) δ 8.21 (dddd,J=2.4, 5.2, 7.2 and 9.2 Hz, 1H), 8.00 (dd, J=2.0 and 7.2 Hz, 1H), 7.65(q, J=8.4 and 14.8 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 7.04 (appt, J=9.6Hz, 1H), 6.65 (s, 1H), 5.36 (s, 2H), 2.07 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −111.40 (1F), −116.00 (1F), −118.36 (1F) ppm. ES-HRMS m/z480.0259 (M+H calcd for C₂₁H₁₇BrF₂NO₅ requires 480.0253).

Example 520

Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxybenzoicacid Step 1 Preparation of methyl 3 amino-4-methoxybenzoate

A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet,stirbar, addition funnel and thermocouple was charged with3-amino-4-methoxy benzoic acid (50 g, 0.299 mol) and methanol (300 mL).The system was cooled to 0 C and acetyl chloride (30 mL, 0.42 mol) wasadded dropwise. The system was warmed to room temperature, the additionfunnel was replaced with a reflux condenser, and was heated to refluxfor 1.5 h. The reaction mixture was cooled to room temperature, quenchedwith saturated aqueous NaHCO₃, and extracted with ethyl acetate. Theorganic extract was washed with brine, dried with Na₂SO₄ andconcentrated in vacuo to give methyl 3-amino-4-methoxybenzoate as a darksolid (47.9 g, 88%). ¹H NMR (400 MHz, CD₃OD) δ 7.40 (t, J=268 Hz, 1H),7.37 (t, J=2.0 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s,3H) ppm. ES-HRMS m/z 182.0826 (M+H calcd for C₉H₁₂ClNO₃ requires182.0812).

Step 2 Preparation of methyl3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methoxybenzoate

A 250 mL round bottomed flask equipped with stirbar, Dean-Stark trap andreflux condenser was charged with the product of Step 1-(23.5 g, 0.129mol), 4-hydroxy-6-methyl-2-pyrone (17.8 g, 0.14 mol), ando-dichlorobenzene (200 mL). The system was immersed in a 170 C oil bathfor 2 h and was then cooled to room temperature. The reaction mixturewas washed with aqueous Na₂CO₃ (28 g, 0.26 mol, 500 mL water). Theaqueous layer was washed with ethyl acetate and then was acidified to pH1-2 with concentrated HCl. This was extracted with ethyl acetate, whichwas then dried with Na₂SO₄ and concentrated in vacuo. The viscous orangeoil was triturated with MeOH to give the title compound as a yellowsolid (1.61 g, 4%). ¹H NMR (400 MHz, CD₃OD) δ 8.14 (dd, J=2.2 and 8.8Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.05 (d, J=2.3Hz, 1H), 5.77 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.90 (s,3H) ppm. ES-HRMS m/z 290.0997 (M+H calcd for C₁₅H₁₆NO₅ requires290.1023).

Step 3 Preparation of methyl3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxybenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 2 (1.6 g, 5.5 mmol) andN,N-dimethyl formamide (10 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91mL, 6 mmol) was added followed by 2,4-difluorobenzyl bromide (0.77 mL, 6mmol). The reaction mixture was stirred at 60 C for 4 h, was poured intosaturated aqueous NaHCO₃ and was extracted with ethyl acetate. Theorganic layer was washed with brine, dried with Na₂SO₄ and concentratedin vacuo to give the title compound as an orange foam (2.13 g, 93%),which was carried on to the next reaction without further purification.¹H NMR (400 MHz, CD₃OD) δ 8.17 (dd, J=2.64 and 11.6 Hz, 1H), 7.82 (td,J=2.7 and 6.8 Hz, 1H), 7.57 (m, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.02 (m,2H), 6.16 (m, 1H), 6.03 (d, J=3.5 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 6H),1.93 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.43 (1F), −116.04 (1F)ppm. ES-HRMS m/z 416.1310 (M+H calcd for C₂₂H₂₀F₂NO₅ requires 416.1304).

Step 4 Preparation of methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxybenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 3 (2.1 g, 5.06 mmol) and N methyl2-pyrrolidine (10 mL). N-Bromo succinimide (1 g, 5.56 mmol) was addedand the reaction mixture was stirred at room temperature for 1 h. Themixture poured into saturated aqueous NaHCO₃ and extracted with ethylacetate. The organic layer was washed with brine, dried with Na₂SO₄, andconcentrated in vacuo. The residue was chromatographed on silica (1:1hexanes; ethyl acetate) to give the title compound as an orange oil(0.77 g, 31%). ¹H NMR (400 MHz, CD₃OD) δ 8.16 (app qd, J=2.5 and 7.2 Hz,1H), 7.84 (d, J=2.6 Hz, 1H), 7.64 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 7.04(appt, J=8.4 Hz, 2H), 6.60 (s, 1H), 5.33 (s, 2H), 3.80 (s, 6H), 1.99 (s,3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.56 (1F), −116.00 (1F) ppm.ES-HRMS m/z 494.0398 (M+H calcd for C₂₂H₁3BrF₂NO₅ requires 494.0409).

Step 5 Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxybenzoicacid

A 100 mL round bottomed flask was charged with the product of Step 4(0.77 g, 1.55 mmol), tetrahydrofuran (10 mL), methanol (5 mL), and water(5 mL). To this slurry was added 2.5 N NaOH (1.2 mL, 3.1 mmol). Thereaction mixture became clear after 30 minutes and the reaction wascomplete in 1 h by LC-MS. The organics were removed on the rotaryevaporator and the remaining solution was acidified to pH 2-3 with 6NHCl. The desired compound was precipitated by the addition of water anddiethyl ether and subsequent filtration. The title compound was isolatedas a white powder (0.60 g, 81w). ¹H NMR (400 MHz, CD₃OD) δ 8.17 (dd,J=2.2 and 8.8 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.64 (q, 1H), 7.29 (d,J=8.8 Hz, 1H), 7.34 (t, J=8.8 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87(s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m/z 480.0259 (M+H calcd forC₂₁H₁₇BrF₂NO₅ requires 480.0253).

Example 521

Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxy-N-methylbenzamideStep 1

To a reaction vessel (borosilicate culture tube) was added Example 520(0.300 g, 0.624 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.31 mmol).N,N-Dimethylformamide (3 mL) was added to the reaction vessel followedby approximately 1.06 g of the polymer bound carbodiimide resin (1.38mmol/g). Additional N,N-dimethylformamide (2 mL) was then added to thereaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. N-Methyl amine (2 mL, 4 mmol) was thenadded to the reaction vessel and the reaction apparatus was orbitallyshaken at room temperature overnight. At this time the reaction wasdiluted with tetrahydrofuran (20 mL) and treated with approximately 2 gof polyamine resin (2.63 mmol/g) and approximately 2.5 g ofmethylisocyanate functionalized polystyrene (1.5 mmol/9) and the orbitalshaking was continued at 200 RPM at room temperature for 3 hours. Thereaction vessel was then opened and the solution phase product wasseparated from the insoluble quenched byproducts by filtration andcollection into a vial. After partially evaporation the insolublebyproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate wasevaporated by blowing N₂ over the vial and the resulting solid wastriturated with diethyl ether to give the desired product as anoff-white solid (0.094 g, 31%). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd,J=2.2 and 8.8 Hz, 1H), 7.64 (m, 2H), 7.28 (d, J=9.2 Hz, 1H), 7.04 (t,J=9.2 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.86 (s, 3H), 2.88 (s, 3H),2.01 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.59 (1F), −116.01 (1F)ppm. ES-HRMS m/z 493.0593 (M+H calcd for C₂₂H₂₀BrF₂N₂O₄ requires493.0569).

Example 522

Preparation of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methoxy-N,N-dimethylbenzamide

The title compound was prepared essentially as in Example 521. ¹H NMR(400 MHz, CD₃OD) δ 7.64 (m, 1H), 7.61 (dd, J=2 and 8.8 Hz, 1H), 7.33 (d,J=2.2 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 2H), 6.59 (s, 1H),5.33 (s, 2H), 3.85 (s, 3H), 3.07 (s, 6H), 2.02 (s, 3H) ppm. ¹⁹F NMR (400MHz, CD₃OD) δ −111.60 (1F), −116.01 (1F) ppm. ES-HRMS m/z 507.0716 (M+Hcalcd for C₂₃H₂₂BrF₂N₂O₄ requires 507.0726).

Example 5231-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride

Step 1 Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzamide

A 250 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (2.58 g, 6.1 mmol), 4-methylmorpholine (2.0 L, 18.3 mmol),2-chloro-4,6-dimethoxy-1,3,5-triazine (1.28 g, 7.3 mmol) andtetrahydrofuran (30 mL). After stirring the mixture for 30 min at 25°C., NH₄OH (15.0 mL) was added. The mixture was stirred for 30 min anddiluted with water. The product precipitated from solution. Theprecipitated was filtered and washed with water and diethyl ether togive the title compound (2.55 g, 78%) as a white solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 8.10 (m, 1H), 7.9 (dd, J=2.1 and 5.2 Hz, 1H), 7.65 (q, 6.7and 8.5 Hz, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.35 (td, J=2.4 and 8.2 Hz, 1H)7.17 (td, J=2 and 6.6 Hz, 1H) 6.78 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm.ES-HRMS m/z 423. 0719 (M+H calcd for C₂₀H₁₅ClF₃N₂O₃ requires 423.0718).

Step 2 Preparation of1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product from step 1-(1.5 g, 3.5 mmol), BH₃.THFcomplex (7.4 mL, 7.4 mmol), and tetrahydrofuran (15 mL). The mixture wasrefluxed for 6 h, allowed to cool to room temperature and quenched withHCl 6N. The organics were evaporated and the remaining aqueous solutionwas saturated with NaOH 2.5N and extracted with dichloromethane. Theorganic phase was dried with Na₂SO₄ and concentrated in vacuo. HCl 6Nwas added, and concentrated in vacuo. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.2(m, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 7.3 (t, J=9.8 Hz, 1H), 7.16 (t, J=8.6Hz, 1H) 6.78 (s, 1H), 5.36 (s, 2H), 4.05 (d, J=5.8 Hz, 2H), 2 (s, 3H)ppm. ES-HRMS m/z 409.0940 (M+H calcd for C₂₀H₁₇ClF₃N₂O₂ requires409.0925).

Example 5243-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide

Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide

The title compound was prepared essentially as in Example 521. ¹H NMR(400 MHz, CD₃OD) δ 8.1 (m, 1H), 7.8 (dd, J=2.3 and 5.1 Hz, 1H), 7.6 (q,J=7.4 and 7.0 Hz, 1H), 7.41 (t, J=8.9 Hz, 1H), 7.04 (m, 2H) 6.7 (s, 1H),5.36 (s, 2H), 4.1 (t, J=5.8 Hz, 1H), 3.7 (d, J=5.1 Hz, 4H) 2.1 (s, 3H)ppm. ES-HRMS m/z 497.1045 (M+H calcd for C₂₃H₂₁ClF₃N₂O₅ requires497.1086).

Examples 525-528

The compounds of Examples 525 528 are prepared by derivitazion ofExample 523. The analytical data are shown below.

M + H ESHRMS Ex. No. R MF Requires m/z Ex. 525 —C(O)CH₃ C₂₂H₁₈ClF₃N₂O₃451.1031 451.1010 Ex. 526 —C(O)CH₂OCH₃ C₂₃H₂₀ClF₃N₂O₄ 481.1136 481.1132Ex. 527 —SO₂CH₃ C₂₁H₁₈ClF₃N₂O₄S 487.0701 487.0679 Ex. 528 —C(O)NH₂C₂₁H₁₆ClF₃N₃O₃ 452.0983 452.0987

NMR characterization of compounds of Examples 525-528 Ex. No. NMR Data525 ¹H NMR (400 MHz, CD₃OD) δ 7.6 (q, J = 7.8 and 7.0 Hz, 1H), 7.5 (m,1H), 7.3 (t, J = 9.0 Hz, 1H), 7.2 (dd, J = 1.9 and 5.1 Hz, 1H), 7.05 (m,2H), 6.65 (s, 1H), 5.36 (s, 2H), 4.39 (s, 2H), 2.1 (s, 3H), 1.98 (s, 3H)ppm 526 ¹H-NMR (400 MHz, CD₃Cl₃) δ 7.45 (q, J = 8.6 and 6.2 Hz, 1H), 7.3(m, 1H), 7.1 (m, 2H), 6.85 (q, J = 6.5 and 1.9 Hz, 1H), 6.78 (td, J =2.7 and 7.8 Hz, 1H), 6.2 (s, 1H), 5.2 (s, 2H), 4.39 (d, J = 6.2 Hz, 2H),4.0 (s, 3H) 2.3 (s, 2H), 2.0 (s, 3H), 1.98 (s, 3H) ppm 527 ¹H NMR (400MHz, CD₃OD) δ 7.49 (q, J = 8.2 and 6.3 Hz, 1H), 7.33 (m, 1H), 7.23 (m,1H), 7.1 (t, J = 8.9, 1H), 6.9 (td, J = 0.78 and 6.6 1H), 6.8 (td, J =2.7 and 6.25 Hz, 1H), 6.2 (s, 1H), 5.2 (s, 2H), 4.2 (s, 2H), 2.8 (s, 3H)2.0 (s, 3H) ppm 528 ¹H NMR (400 MHz, (CD₃)₂SO) δ 7.61 (q, J = 8.9 and6.6 Hz, 1H), 7.38(d, J = 7.8 Hz, 1H), 7.3 (d, J = 10.2 Hz, 1H) 7.21 (d,J = 7.4 Hz, 1H), 7.1 (t, J = 8.6 Hz, 1H), 6.71 (s, 1H), 6.5 (t, J = 5.8Hz, 1H), 5.56 (s, 2H), 5.3 (s, 2H), 4.18 (d, J = 6.25 Hz, 2H), 3.61 (s,1H), 1.98 (s, 3H) ppm

Example 529

2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile

2-(bromomethyl)-5-fluorobenzonitrile (3.47 g, 16.2 mmol),3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one(3.15 g, 11.6 mmol), K₂CO₃ (2.56 g, 18.6 mmol), and 18-crown-6 (0.15 g)were dissolved in N,N-dimethylacetamide (25 mL). Reaction mixturestirred on 60° C. oil bath for 4 hours. Solvent removed by distillation.Reaction neutralized with 5% citric acid. The solid product was washedwith hexane followed by 30% EtOAc/hexane. Filtered a brown solid (5.2 g,79% yield).

¹H NMR (CD₃OD/400 MHz) δ7.82 (m, 2H), 7.61 (m, 4H), 6.75 (s, 1H), 5.49(s, 2H), 2.13 (s, 3H). ESHRMS m/z 405.0616 (M+H C₂₀H₁₃ClF₃N₂O₂ requires405.0612).

Example 530

4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate

BH₃THF (17.8 mL, 17.8 mmol) was added dropwise to a chilled (0° C.)solution of2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile(3.61 g, 8.92 mmol) in THF (30 mL). Following the addition, the reactionwas heated at 60° C. for 1.5 hours. The reaction was quenched with MeOH,the solvent evaporated, and the crude product purified by prep HPLC. Theproduct was isolated by freeze-drying and evaporation of the solvent togive a white solid (1.52 g, 32.6%). ¹H NMR (CD₃OD/400 MHz) δ7.62 (m,2H), 7.32 (m, 1H), 7.25 (tr, 2H, J=8.00 Hz), 7.18 (m, 1H), 6.78 (s, 1H),5.43 (s, 1H), 4.22 (s, 1H), 2.14 (s, 3H). ESHRMS m/z 409.0900 (M+HC₂₀H₁₇N₂O₂F₃Cl requires 409.0925).

Examples 531-551

The compounds of Examples 531-551 are prepared by derivitazion ofExample 530. The analytical data are shown below.

Compound M + H ESHRMS No. R MF Requires m/z Ex. 531 —OCH₃ C₂₂H₁₈ClF₃N₂O₄467.0980 467.0985 Ex. 532 —CF₃ C₂₂H₁₅ClF₆N₂O₃ 505.0748 505.0754 Ex. 533—O-isopropyl C₂₄H₂₂ClF₃N₂O₄ 495.1293 495.1304 Ex. 534 —NH—CH₂CH₃C₂₃H₂₁ClF₃N₃O₃ 480.1296 480.1277 Ex. 535 —O-tetrahydrofuran-3-ylC₂₅H₂₂ClF₃N₂O₅ 523.1242 523.1282 Ex. 536 —O-propyl C₂₄H₂₂ClF₃N₂O₄495.1293 495.1338 Ex. 537 —O—CH₂CH═CH₂ C₂₄H₂₀ClF₃N₂O₄ 493.1136 493.1116Ex. 538 —O—CH₂C≡CH C₂₄H₁₈ClF₃N₂O₄ 491.0980 491.0961 Ex. 539 —O-tButylC₂₅H₂₄ClF₃N₂O₄ 509.1449 509.1436 Ex. 540 —NH-tButyl C₂₅H₂₅ClF₃N₃O₃508.1609 508.1574 Ex. 541 —SO₂CH₂CH₂CH₃ C₂₃H₂₂ClF₃N₂O₄S 515.1014515.0979 Ex. 542 —SO₂CH₂CH₃ Ex. 543 —NH-isopropyl C₂₄H₂₃ClF₃N₃O₃494.1453 494.1456 Ex. 544 —CH₂OCH₃ C₂₃H₂₀ClF₃N₂O₄ 481.1136 481.1174 Ex.545 —NHCH₃ C₂₂H₂₀ClF₃N₃O₃ 466.1140 466.1141 Ex. 546 —N(CH₃) (tButyl)C₂₆H₂₇ClF₃N₃O₃ 522.1766 522.1737 Ex. 547 —NH(cyclopropyl) C₂₄H₂₁ClF₃N₃O₃492.1296 492.1285 Ex. 548 —NHCH₂CF₃ C₂₃H₁₇ClF₆N₃O₃ 534.1014 534.1005 Ex.549 NHCH₂(cyclopropyl) C₂₅H₂₃ClF₃N₃O₃ 506.1453 506.1432 Ex. 550—NHCH₂(tButyl) C₂₆H₂₇ClF₃N₃O₃ 522.1766 522.1740 Ex. 551 —N(CH₃)₂C₂₃H₂₂ClF₃N₃O₃ 480.1296 480.1307

NMR characterization of compounds of Examples 531-551 Ex. No. NMR data531 ¹H NMR (CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.53 (m, 1H), 7.24 (t, 2H, J= 8.00 Hz), 7.14 (m, 1H), 7.05 (m, 1H), 5.74 (s, 1H), 5.40 (s, 2H), 4.42(s, 2H), 3.63 (s, 3H), 2.12 (s, 3H) 532 ¹H NMR CD₃OD/400 MHz) δ 7.59 (m,2H), 7.24 (t, 2H, J = 8.00 Hz), 7.11 (m, 2H), 5.73 (s, 1H), 5.43 (s.2H), 4.62 (s, 2H), 2.12 (s, 3H) 533 ¹H NMR (CD₃OD/400 MHz) δ 7.61 (m,1H), 7.53 (m, 1H), 7.24 (t, 2H, J = 7.60 Hz), 7.13 (m, 1H), 7.05 (m,1H), 6.74 (s, 1H), 5.40 (s, 2H), 4.81 (m, 1H), 4.41 (s, 2H), 2.12 (s,3H), 1.21 (d, 6H, J = 6.00 Hz) 534 ¹H NMR CD₃OD/400 MHz) δ 7.61 (m, 1H),7.52 (m, 1H), 7.24 (t, 2H, J = 0.80 Hz), 7.13 (m, 1H), 7.03 (m, 1H),6.73 (s, 1H), 5.39 (s, 2H), 4.44 (s, 2H), 3.12 (q, 2H, J = 7.20 Hz),2.12 (s, 3H), 1.08 (t, 3H, J = 7.20 Hz) 535 ¹H NMR (CD₃OD/300 MHz) δ7.62 (m, 1H), 7.54 (m, 1H), 7.25 (t, 2H, J = 8.4 Hz), 7.15 (m, 1H), 7.07(m, 1H), 6.75 (s, 1H), 5.41 (s, 2H), 5.15 (s br, 1H), 4.44 (s, 2H), 3.82(m, 4H), 2.13 (s, 4H), 2.03 (s br, 1H) 536 ¹H NMR (CD₃OD/300 MHz) δ 7.62(m, 1H), 7.54 (m, 1H), 7.25 (t, 2H, J = 8.1 Hz), 7.15 (m, 1H), 7.06 (m,1H), 6.74 (s, 1H), 5.41 (s, 2H), 4.43 (s, 2H), 3.98 (t, 2H, J = 6.6 Hz),2.13 (s, 3H), 1.63 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz) 537 ¹H NMR(CD₃OD/300 MHz) δ 7.62 (m, 1H), 7.54 (m, 1H), 7.25 (t, 2H, J = 8.4 Hz),7.14 (m, 1H), 7.07 (m, 1H), 6.74 (s, 1H), 5.92 (m br, 1H), 5.41 (s, 2H),5.29 (d, 1H, J = 17.7 Hz), 5.17 (d, 1H, J = 10.5 Hz), 4.63 (s, 1H), 4.53(d, 2H, J = 5.4 Hz), 4.44 (s, 2H), 2.13 (s, 3H) 538 ¹H NMR (CD₃OD/400MHz) δ 7.61 (m, 1H), 7.53 (m, 1H), 7.24 (t, 2H, J = 7.6 Hz), 7.14 (m,1H), 7.06 (m, 1H), 6.74 (s, 1H), 5.41 (s, 2H), 4.65 (d, 2H, J = 2.4 Hz),4.44 (s, 2H), 2.86 (t, 1H, J = 2.4 Hz), 2.12 (s, 3H) 539 ¹H NMR(CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.53 (m, 1H), 7.24 (tr, 2H, J = 8.40),7.12 (m, 1H), 7.05 (m, 1H), 6.74 (s, 1H), 5.39 (s, 2H), 4.36 (s, 2H),2.12 (s, 3H), 1.43 (s, 9H) 540 ¹H NMR (CD₃OD/400 MHz) δ 7.61 (m, 1H),7.53 (m, 1H), 7.24 (tr, 2H, J = 8.00 Hz), 7.12 (m, 1H), 7.04 (m, 1H),6.73 (s, 1H), 5.37 (s, 2H), 4.39 (s, 2H), 2.12 (s, 3H), 1.28 (s, 9H) 541¹H NMR (CD₃OD/300 MHz) δ 7.59 (m, 2H), 7.26 (m, 3H), 7.11 (m, 1H), 6.75(s, 1H), 5.46 (s, 2H), 4.40 (s, 2H), 3.02 (m, 2H), 2.12 (s, 3H), 1.80(m, 2H), 1.03 (tr, 3H, J = 7.50 MHz) 542 ¹H NMR (CD₃OD/400 MHz) δ 7.58(m, 2H), 7.26 (m, 3H), 7.10 (m, 1H), 6.74 (s, 1H), 5.45 (s, 2H), 4.39(s, 2H), 3.06 (q, 2H, J = 7.60 Hz), 2.11 (s, 3H), 1.31 (t, 3H, J = 7.2Hz) 543 ¹H NMR (CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.52 (m, 1H), 7.24 (t,2H. J = 8.40 Hz), 7.12 (m, 1H), 7.04 (m, 1H), 6.73 (s, 1H), 5.39 (s,2H), 4.44 (s, 2H), 3.77 (m, 1H), 2.12 (s, 3H), 1.10 (d, 6h, J = 6.40 Hz)544 ¹H NMR (CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.54 (m, 1H), 7.24 (t, 2H, J= 7.6 Hz), 7.15 (m, 1H), 7.06 (m, 1H), 6.74 (s, 1H), 5.43 (s, 2H), 4.55(s, 2H), 3.92 (s, 2H), 3.40 (s, 3H), 2.12 (s, 3H) 545 ¹H NMR (CD₃OD/300MHz) δ 7.63 (m, 1H), 7.54 (m, 1H), 7.26 (t, 2H, J = 8.7 Hz), 7.15 (m,1H), 7.05 (m, 1H), 6.75 (s, 1H), 5.42 (s, 2H), 4.47 (s, 2H), 2.70 (s,3H), 2.14 (s, 3H) 546 ¹H NNMR (CD₃OD/300 MHz) δ 7.63 (m, 1H), 7.53 (m,1H), 7.25 (t, 2H, J = 9.0 Hz), 7.14 (m, 1H), 7.04 (m, 1H), 6.76 (s, 1H),5.41 (s, 2H), 4.44 (s, 2H), 2.90 (s, 3H), 2.13 (s, 3H), 1.39 (s, 9H) 547¹H NNMR (CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.52 (m, 1H), 7.24 (t, 2H, J =7.6 Hz), 7.14 (m, 1H), 7.03 (m, 1H), 6.74 (s, 1H), 5.41 (s, 2H), 4.47(s, 2H), 2.46 (m, 1H), 2.12 (s, 3H), 0.68 (q, 2H, J = 5.2 Hz), 0.46 (m,2H) 548 ¹H NNMR (CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.53 (m, 1H), 7.24 (t,2H, J = 8.0 Hz), 7.12 (m, 1H), 7.04 (m, 1H), 6.73 (s, 1H), 5.39 (s, 2H),4.47(s, 2H), 3.79 (q, 2H, J = 9.6 Hz), 2.12 (s, 3H) 549 ¹H NNMR(CD₃OD/400 MHz) δ 7.61 (m, 1H), 7.52 (m, 1H), 7.24 (t, 2H, J = 8.4 Hz),7.14 (m, 1H), 7.04 (m, 1H), 6.73 (s, 1H), 5.39 (s, 2H), 4.45 (s, 2H),2.96 (d, 2H, J = 6.8 Hz), 2.12 (s, 3H), 0.93 (m, 1H), 0.44 (m, 2H), 0.16(q, 2H, J = 4.8 Hz) 550 ¹H NNMR (CD₃OD/400 MHz) 57.61 (m, 1H), 7.53 (m,1H), 7.24 (t, 2H, J = 8.0Hz), 7.14 (m, 1H), 7.04 (m, 1H), 6.73 (s, 1H),5.39 (s, 2H), 4.46 (s, 2H), 2.92 (d, 2H, J = 4.8 Hz), 2.12 (s, 3H), 0.87(s, 9H) 551 ¹H NNMR (CD₃OD/300 MHz) δ 7.62 (m, 1H), 7.52 (m, 1H), 7.25(t, 2H, J = 8.7 Hz), 7.15 (m, 1H), 7.04 (m, 1H), 6.75 (s, 1H), 5.42 (s,2H), 4.48 (s, 2H), 2.90 (s, 6H), 2.14 (s, 3H)

¹H NMR (CD₃OD/400 MHz) δ7.58 (m, 2H), 7.26 (m, 3H), 7.10 (m, 1H), 6.74(s, 1H), 5.45 (s, 2H), 4.39 (s, 2H), 3.06 (q, 2H, J=7.60 Hz), 2.11 (s,3H), 1.31 (t, 3H, J=7.2 Hz)¹H NMR (CD₃OD 3 300 MHz) δ7.63 (m, 1H), 7.54(m, 1H), 7.26 (t, 2H, J=8.7 Hz), 7.15 (m, 1H), 7.05 (m, 1H), 6.75 (s,1H), 5.42 (s, 2H), 4.47 (s, 2H), 2.70 (s, 3H), 2.14 (s, 3H). ESHRMS m/z466.1141 (M+H C₂₂H₂₀ClF₃N₃O₃ requires 466.1140).

Example 552

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-oneStep 1: Preparation of methyl 6-methylnicotinate 1-oxide

Methyl 6-methylnicotinate (6.0 g, 39.7 mmol) was added intodichloromethane (100 mL) in the round bottom flask under nitrogen.3-chloroperoxybenzoic acid (10.0 g, 57.9 mmol) was then added into theflask and stirred for 5 hour. Saturated sodium bicarbonate solution (100ml) was added into the reaction and the mixture was transferred toseparatory funnel. Additional 200 mL of dichloromethane was added intothe funnel and obtained the organic layer. The organic layer was washedwith water (150 mL) and dried over anhydrous magnesium sulfate. Theresulting solution was evaporated to yield white solid (6 g, 90%).LC/MS, t_(r)=0.33 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 168 (M+H). ES-HRMSm/z 168.0628 (M+H calcd for C₈H₁₀NO₃ requires 168.0655).

Step 2: Preparation of methyl 6-(chloromethyl)nicotinate

Methyl 6-methylnicotinate 1-oxide (from Step 1) (6.0 g, 35.9 mmol) wasadded into the p-toluenesulfonyl chloride (10 g, 52.4 mmol) in 100 mL of1,4-dioxane. The mixture was heated to reflux for 20 hours. Saturatedsodium bicarbonate solution (200 ml) was added into the reaction and themixture was transferred to separatory funnel. The compound was extractedusing ethyl acetate (300 ml×2) and the combined ethyl acetate solutionwas dried over magnesium sulfate and evaporated to black solid (5.2 g,78%). LC/MS, t_(r)=1.52 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 186(M+H). ES-HRMS m/z 186.0314 (M+H calcd for C₈H₉ClNO₂ requires 186.0316).

Step 3: Preparation of methyl6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate

Methyl 6-(chloromethyl)nicotinate (from step 2). (2 g, 10.8 mmol) wasadded into 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one in 20mL of dimethyl formamide followed by addition of cesium carbonate (5 g,15.3 mmol). The mixture was heated to 100 C for 20 hours. It was cooledto room temperature and added 400 mL of water. Brown precipitate cameout of from solution. It was filtered and rinsed with water (200 mL×3)and dried to obtain 4 g of solid. The product was purified using aGilson Reversed Phase preparative chromatography to obtain white solid(1.4 g, 32%). ¹H NMR (400 MHz, CDCl₃) δ 9.09 (d, J=1.48 Hz, 1H), 8.19(dd, J=6.04, 2.15 Hz, 1H), 7.37 (app q, J=8.32 Hz, 1H), 7.25 (d, J=8.33Hz, 1H), 6.84 (m, 2H), 5.94 (d, J=2.82 Hz, 1H), 5.83 (d, J=2.15 Hz, 1H),5.36 (s, 2H), 4.97 (s, 2H), 3.90 (s, 3H), 2.27 (s, 3H); LC/MS,t_(r)=2.30 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 401 (M+H). ES-HRMSm/z 401.1307 (M+H calcd for C₂₁H₁₉F₂N₂O₄ requires 401.1307).

Step 4: Preparation of the Title Compound

3 molar solution of methyl magnesium bromide in ether (5 mL, 15 mmol)was added into 5 ml of anhydrous tetrahydrofuran in the round bottomflaks under nitrogen. The mixture was cooled to 0° C. Methyl6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate(from Step 3) (300 mg, 0.75 mmol)was dissolved in 5 ml of anhydroustetrahydrofuran in dropper funnel and the solution was slowly added intocold methyl magnesium bromide solution in the round bottom flask. Afterthe addition, the mixture was continue stirring at 0 C for 30 minute andcold solution of saturated ammonium chloride (100 ml) was added slowlyinto the reaction mixture. The mixture was transferred to separatoryfunnel and the product was extracted with ethyl acetate (200 ml×2). Thecombined ethyl acetate solution was dried over anhydrous magnesiumsulfate and evaporated to dryness. The resulting residue (220 mg) wasadded into 10 ml of dichloromethane followed by addition of N-bromosuccinimide (100 mg, 0.56 mmol). The solution was stirred at roomtemperature for 3 hours. Saturated sodium bicarbonate solution (100 ml)was added into the reaction mixture and it was transferred to separatoryfunnel. The product was extracted with ethyl acetate (200 ml X₂). Thecombined ethyl acetate solution was dried over anhydrous magnesiumsulfate and evaporated to dryness.

¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=1.88 Hz, 1H), 7.73 (dd, J=5.77,2.42 Hz, 1H), 7.55 (app q, J=6.31 Hz, 1H), 7.30 (d, J=8.19b Hz, 1H),6.93 (m, 1H), 6.84 (m, 1H), 6.00 (s, 1H), 5.37 (s, 2H), 5.19 (s, 2H),2.48 (s, 3H), 1.56 (s, 6H); LC/MS, t_(r)=2.29 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0791 (M+H calcd forC₂₂H₂₂BrF₂N₂O₃ requires 479.0776).

Example 553

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-one

Methyl6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate(from preparation of step 3) (350 mg, 0.87 mmol) was added intoanhydrous tetrahydrofuran (15 ml) and the solution was cooled to −78 C.Into the cold solution, was added lithium aluminum hydride (100 mg, 2.6mmol). After the addition, the reaction mixture was warm to 0 C andcontinue stirring for one additional hour. Potassium hydrogen sulfate (1N solution, 150 ml) was added slowly into the reaction mixture to quenchthe reaction. The resulting mixture was transferred to a separatoryfunnel and the product was extracted with ethyl acetate (200 ml×2). Thecombine ethyl acetate solution was dried over anhydrous magnesiumsulfate and evaporated to dryness. LC/MS, t_(r)=1.88 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 373 (M+H)

Step 2: Preparation of the Title Compound

4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(1H)-one(from step 1). (230 mg, 0.62 mmol) was added into 10 ml ofdichloromethane followed by addition of N-bromo succinimide (110 mg,0.62 mmol). The solution was stirred at room temperature for 3 hours.Saturated sodium bicarbonate solution (100 ml) was added into thereaction mixture and it was transferred to a separatory funnel Theproduct was extracted with ethyl acetate (200 ml×2). The combined ethylacetate solution was dried over anhydrous magnesium sulfate andevaporated to dryness. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (app s, 1H), 7.64(dd, J=5.77, 2.29 Hz, 1H), 7.55 (app q, J=6.45 Hz, 1H), 7.33 (d, J=6.05Hz, 1H), 6.93 (m, 1H), 6.84 (m, 1H), 6.00 (s, 1H), 5.39 (s, 2H), 5.19(s, 2H), 4 68 (s, 2H), 2.46 (s, 3H); LC/MS, t_(r)=2.01 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 451 (M+H)

Example 554

6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylnicotinamideStep 1: Preparation of methyl6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate

Methyl6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate(350 mg, 0.87 mmol) (1.0 g, 2.5 mmol) was added into 150 ml ofdichloromethane followed by addition of N-bromo succinimide (500 mg, 2.8mmol). The solution was stirred at room temperature for 3 hours.Saturated sodium bicarbonate solution (300 ml) was added into thereaction mixture and it was transferred to a separatory funnel. Theproduct was extracted with ethyl acetate (500 ml X₂). The combined ethylacetate solution was dried over anhydrous magnesium sulfate andevaporated to dryness. ¹H NMR (400 MHz, CDCl₃) δ 9.08 (app d, J=2.15 Hz,1H), 8.21 (dd, J=6.04, 2.15 Hz, 1H), 7.55 (app qt, J=6.31 Hz, 1H), 7.41(d, J=6.31 Hz, 1H), 6.91 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.42 (s,2H), 5.19 (s, 2H), 3.91 (s, 3H), 2.45 (s, 3H); LC/MS, t_(r)=2.85 minutes(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0415 (M+H calcdfor C₂₁H₁₈BrF₂N₂O₄ requires 479.0413).

Step 2: Preparation of6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinicacid

Methyl6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate(from step 1) (1.0 g, 2.1 mmol) was added into the mixture of 100 mltetrahydrofuran and 10 ml of methanol followed by addition of 2.5 Nsodium hydroxide (0.85 ml, 2.1 mmol). The solution was heated to 50 Cfor 2 hours. After the solution was cooled to room temperature andevaporate to completely dried residue. The residue was added into 50 mlof tetrahydrofuran and 4 N HCl in 1,4-dioxane (0.52 ml, 2.1 mmol) andstirred the mixture for 30 minute. The mixture was evaporate to dryness.The residue was added 20 ml water and the aqueous solution wasneutralized to exactly ph 7 by addition of saturated sodium bicarbonatesolution drop wise. The resulting heterogeneous mixture was left standedfor 20 hours. Filtered, rinsed with water (30 ml×3) and dried over highvacuum oven to afford white solid (950 mg, 97%).

¹H NMR (400 MHz, CDCl₃ and CD₃OD) δ 8.98 (app br s, 1H), 8.15 (dd,J=6.17, 2.02 Hz, 1H), 7.45 (app q, J=6.58 Hz, 1H), 7.21 (d, J=8.19 Hz,1H), 6.84 (m, 1H), 6.76 (m, 1H), 6.04 (s, 1H), 5.35 (s, 2H), 5.12 (s,2H), 2.32 (s, 3H); LC/MS, t_(r)=2.48 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 465 (M+H). ES-HRMS m/z 465.0254 (M+H calcd forC₂₀H₁₆BrF₂N₂O₄ requires 465.0256).

Step 3: Preparation of the Title Compound

6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinicacid (from step 2) (230 mg, 0.5 mmol) was added into the1-hydroxybenzotriazole (101 mg, 0.75 mmol) in 5 ml ofN,N-dimethylforamide. 4-methyl morpholine (0.16 ml, 1.5 mmol) was addedinto the mixture followed by addition of1-(3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (143 mg,0.75 mmol). Stirred the mixture for 30 minute to become homogenoussolution. To that homogenous solution, was added 2-(methylamino) ethanol(0.06 ml, 0.75 mmol) and the mixture was stirred for 20 hours. Water(150 ml) was added into the reaction mixture and the product wasextracted using ethyl acetate (400 ml X₂). The combined ethyl acetatesolution was dried over anhydrous magnesium sulfate and evaporated todryness. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (app br s, 1H), 7.80 (br d,J=7.92 Hz, 1H), 7.64 (app q, J=6.58 Hz, 1H), 7.30 (m, 2H), 7.15 (m, 1H),6.56 (s, 1H), 5.39 (s, 2H), 5.28 (s, 2H), 3.46 (m, 2H), 3.23 (m, 2H)2.93 (m, 3H), 2.36 (s, 3H); LC/MS, t_(r)=2.29 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-HRMS m/z 522.0850 (M+H calcd for C₂₃H₂₃BrF₂N₃O₄ requires522.0835).

Example 555

6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)nicotinamide

Following the method of Example 554 (step 3) and substituting2-(methylamino)ethanol for the ethanolamine obtained the title compoundas a white solid (79% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.93 (d, J=2.01Hz, 1H), 8.21 (dd, J=6.04, 2.21 Hz, 1H), 7.67 (app q, J=6.44 Hz, 1H),7.39 (d, J=8.06 Hz, 1H), 7.08 (m, 2H), 6.58 (s, 1H), 5.55 (s, 2H), 5.35(s, 2H), 3.74 (app t, J=5.73 Hz, 2H), 3.53 (app t, J=5.73 Hz, 2H), 2.49(s, 3H); LC/MS, t_(r)=2.26 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-HRMS m/z508.0673 (M+H calcd for C₂₂H₂₁BrF₂N₃O₄ requires 508.0678).

Example 556

6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylnicotinamide

Following the method of Example 554 (step 3) and substitutingdimethylamine for the ethanolamine obtained the title compound as awhite solid (75% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=1.62 Hz,1H), 7.68 (dd, J=5.77, 2.15 Hz, 1H), 7.55 (app q, J=6.45 Hz, 1H), 7.37(d, J=8.06 Hz, 1H), 6.93 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.40 (s,2H), 5.20 (s, 2H), 3.09 (s, 3H), 2.97 (s, 3H), 2.45 (s, 3H); LC/MS,t_(r)=2.45 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-HRMS m/z 492.0710 (M+Hcalcd for C₂₂H₂₁BrF₂N₃O₃ requires 492.0729).

Example 557

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-oneStep 1: Preparation of4-hydroxy-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one

4-hydroxy-6-methyl-2-pyrone (10 g, 79.3 mmol) was added into the2-(trifluoromethyl)aniline (14 ml, 111.3 mmol) in 10 ml of1,2-dichlorobenzene in a round bottom flask. The mixture was then placedin a pre-heated oil bath at 165 C. After 30 minute of heating, themixture was cooled to room temperature and added 250 ml of saturatedsodium bicarbonate solution. The mixture was stirred at room temperaturefor 15 minutes and transferred to a separatory funnel. Ethyl acetate(300 ml) was added into the separatory funnel and partitions the layers.The aqueous layer was obtained and the organic layer was added 200 ml ofsaturated sodium bicarbonate solution. The aqueous layer was obtainedagain and the combined aqueous solution was neutralized with HClsolution. Upon neutralization, white solid precipitated out of thesolution. Filtered the solid, rinsed with water (100 ml X₅) and driedover high vacuum oven to obtain the white solid (7.5 g, 35.5%). LC/MS,t_(r)=1.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 270 (M+H).

Step 2: Preparation of4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one

4-hydroxy-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one (fromStep 1) (7.3 g, 27.1 mmol) was added into 3,4-difluorobenzyl bromide(5.5 g, 26.5 mmol) in 60 ml of dimethyl formamide. The mixture wascooled to 0 C and cesium carbonate (20 g, 61.3 mmol) was added into themixture. After the addition, the mixture was warmed to room temperatureand stirred for 4 hours. Water (500 ml) was added into the reactionmixture. Yellow solid came out of solution. Filtered and rinsed withwater (200 ml×2) to obtain the yellow solid. Dissolved the solid inethyl acetate (500 ml) and water (300 ml) and transfer to a separatoryfunnel and obtained the organic layer. The organic layer was washedagain with water (200 ml) and dried over anhydrous magnesium sulfate.The organic solution was evaporated to dryness. ¹H NMR (400 MHz, CDCl₃)δ 7.82 (d, J=7.65 Hz, 1H), 7.7 (t, J=7.52 Hz, 1H), 7.58 (t, J=7.65 Hz,1H), 7.42 (q, J=6.45 Hz, 1H), 7.27 (d, J=7.78 Hz, 2H), 6.89 (m, 2H),5.95 (app d, J=2.42 Hz, 1H), 5.90 (app d, J=2.42 Hz, 1H), 5.01 (app d,J=2.94 Hz, 2H), 1.86 (s, 3H); LC/MS, t_(r)=2.74 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 396 (M+H)

Step 3: Preparation of the Title Compound

N-bromosuccinimide (0.24 g, 1.36 mmol) was added into4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one(0.54 g, 1.36 mmol) in 20 ml of dichloromethane. The mixture was stirredat room temperature for 2 hours. Saturated sodium bicarbonate solution(150 ml) was added into the reaction mixture and the combine solutionwas transferred to a separatory funnel. The product was extracted withethyl acetate (250 ml). The ethyl acetate solution was dried overanhydrous magnesium sulfate and evaporated to dryness. ¹H NMR (400 MHz,CDCl₃) δ 7.82 (d, J=7.25 Hz, 1H), 7.7 (app t, J=7.66 Hz, 1H), 7.60 (m,2H), 7.26 (s, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 6.09 (s, 1H), 5.25 (appd, J=3.35 Hz, 2H), 1.94 (s, 3H); LC/MS, t_(r)=2.84 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-HRMS m/z 474.0113 (M+H calcd for C₂₀H₁₄BrF₅NO₂ requires474.0123).

Example 558

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one

Step 1: To a room temperature solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one(1.00 g, 1.76 mmol) in anhydrous THF (12 mL) was added, sequentially,tributyl(vinyl)tin (1.21 g, 3.81 mmol) andtetrakis(triphenylphosphine)palladium (236 mg, 0.204 mmol) under anargon stream. The reaction vessel was then equipped with a refluxcondenser and the reaction system purged with an argon flow. Theresulting yellow solution was heated to 68° C. and stirred under apositive pressure of argon for 12.0 hours until complete disappearanceof starting material by LCMS analysis. The reaction mixture wasconcentrated in vacuo and the resulting dark residue was subjected toSiO₂ chromatography with ethyl acetate/hexanes (3:7) to furnish areddish solid. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (app q, J=7.8 Hz, 1H),7.45 (app tt, J=8.4, 6.2, 1H), 7.09 (app t, J=8.8 Hz, 2H), 6.90 (app t,J=8.0 Hz, 1H), 6.83 (app dt, J=6.8, 2.5 Hz, 1H), 6.51 (dd, J=17.7, 11.4Hz, 1H), 5.53 (dd, J=11.4, 1.5 Hz, 1H), 5.41 (dd, J=17.8, 1.5 Hz, 1H),5.09 (br s, 2H), 2.09 (s, 3H); LC/MS C-18 column, t_(r)=3.20 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254nm, at 50° C.). ES-MS m/z 468 (M+H). ES-HRMS m/z 468.0210 (M+H calcd forC₂₁H₁₅BrF₄NO₂ requires 468.0217).

Example 560

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-dihydroxyethyl)-6-methylpyridin-2-(1H)-one

Step 1: To a room temperature solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one(0.970 g, 2.07 mmol) in water/acetone 1:3 (8.7 mL) was added,sequentially, osmium tetroxide (0.110 g, 0.433 mmol) and N-methylmorpholine oxide (1.32 g, 11.2 mmol). The resulting solution was stirredfor one hour until complete consumption of starting material by LCMSanalysis, and the reaction was concentrated in vacuo. The resulting darkresidue was subjected to SiO₂ chromatography with ethyl acetate/hexanes(3:7) to furnish a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q, J=8.2Hz, 1H), 7.45 (ddd, J=14.7, 8.5, 6.8 Hz, 1H), 7.08 (app t, J=8.5 Hz,2H), 6.94 (app t, J=8.2 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (AB-q,J=10.6 Hz, Δ=38.3 Hz, 2H), 5.07 (dd, J=9.1, 3.8 Hz, 1H), 3.83 (t, J=10.8Hz, 1H), 3.60 (dd, J=11.4, 3.9 Hz, 1H), 2.94 (br s, 1H), 2.16 (s, 3H);LC/MS C-18 column, t_(r)=2.26 minutes (5 to 95% acetonitrile/water over5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 502(M+H). ES-HRMS m/z 502.0276 (M+H calcd for C₂₁H₁₇BrF₄NO₄ requires502.0272).

Example 561

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(1H)-one

Step 1: To a −20° C. solution of5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde(0.659 g, 1.40 mmol) in methanol (10 mL) was added, portionwise, solidsodium borohyride (3.6 g, 96 mmol) over one hour until completeconsumption of starting material by LCMS analysis. Next, the reactionmixture was diluted with 500 mL of ethyl acetate and washed with 3×200mL of water. The resulting organic extract was Na₂SO₄ dried, filtered,and concentrated in vacuo to approximately 100 mL volume. The resultingliquid was diluted with hexanes (100 mL) to furnish an amorphous solidthat was collected and dried at 1 mm Hg vacuum to furnish (620 mg, 94%)of the desired product. ¹H NMR (400 MHz, d₄-MeOH) δ 7.70 (app q, J=8.3Hz, 1H), 7.62 (app tt, J=10.4, 6.3 Hz, 1H), 7.25 (app t, J=8.6 Hz, 2H),7.03 (app t, J=8.6 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (s, 2H),4.58 (s, 2H), 2.17 (s, 3H); LC/MS C-18 column, t_(r)=2.49 minutes (5 to95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm,at 50° C.). ES-MS m/z 472 (M+H). ES-HRMS m/z 472.0152 (M+H calcd forC₂₀H₁₅BrF₄NO₃ requires 472.0166).

Example 562

4-(benzyloxy)-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-(benzyloxy)-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one

To a briskly stirred room temperature solution of1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (1.43 g, 6.03mmol) in dimethylformamide (4.6 mL) was added sequentially K₂CO₃ (2.01g, 14.5 mmol) and benzyl bromide (2.40 mL, 20.2 mmol). The resultingsuspension was stirred for 6.5 hours until complete consumption ofstarting material by LCMS analysis. The reaction was then diluted withethyl acetate (200 mL) and brine washed (3×200 mL). The resultingorganic extract was Na₂SO₄ dried, filtered, and concentrated in vacuo toapproximately 100 mL volume. The resulting mother liquor rapidlyprecipitated and furnished an amorphous solid that was collected anddried at 1 mm Hg vacuum to provide a solid (1.62 g, 82%). ¹H NMR (300MHz, d₄-MeOH) δ 7.62 (app tt, J=8.6, 6.4 Hz, 1H), 7.52-7.32 (m, 4H),7.30-7.12 (m, 3H), 6.27 (d, J=1.6 Hz, 1H), 6.04 (d, J=2.6 Hz, 1H), 5.18(s, 2H), 2.06 (s, 3H). LC/MS C-18 column, t_(r)=2.51 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 328 (M+H). ES-HRMS m/z 328.1179 (M+H calcd forC₁₉H₁₆F₂NO₂ requires 328.1144).

Step 2. To a room temperature solution of4-(benzyloxy)-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one (1.52 g,4.64 mmol) in methylene chloride (15 mL) was added solidN-bromosuccinimide (2.01 g, 11.3 mmol) and the resulting reddishsolution was stirred for 4.0 hours. At this time the reaction wasdiluted with ethyl acetate (400 mL) and washed with sodium sulfite (5%aqueous solution, 100 mL) and brine (3×200 mL). The resulting organicextracts were Na₂SO₄ dried, filtered, and concentrated in vacuo toapproximately 60 mL volume. The resulting mother liquor rapidlyprecipitated and furnished an amorphous solid that was collected anddried at 1 mm Hg vacuum to provide a solid (1.70 g, 91%). ¹H NMR (300MHz, d₄-MeOH) δ 7.64 (app tt, J=8.6, 6.4 Hz, 1H), 7.57 (br d, J=7.1 Hz,1H), 7.50-7.34 (m, 4H), 7.27 (app t, J=8.0 Hz, 1H), 7.26-7.21 (m, 1H),6.66 (s, 1H), 5.40 (s, 2H), 2.12 (s, 3H); LC/MS C-18 column, t_(r)=2.63minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 406 (M+H). ES-HRMS m/z 406.0228(M+H calcd for C₁₉H₁₅BrF₂NO₂ requires 406.0249).

Example 563

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]methylcarbamate

Step 1: To a room temperature solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(1H)-one(76.2 mg, 0.161 mmol) in methylene chloride (0.4 mL) was added asolution of trichloroacetyl isocyanate (toluene, 0.60 M, 0.5 mL, 0.30mmol). The resulting solution was stirred for one hour until completeconsumption of starting material by LCMS analysis. The reaction mixturewas then directly applied to Al₂O₃ (0.5 g of Broeckman-activity type I)and the slurry was matured for three hours. At this time, the Al₂O₃ plugwas flushed with ethyl acetate/methanol (95:5) and the resulting motherliquor was concentrated to a residue that was subjected to SiO₂chromatography using ethyl acetate/hexanes (1:1) to furnish a whitesolid (71.0 mg, 85%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.71-7.59 (m, 2H),7.26 (app t, J=8.5 Hz, 2H), 7.02 (app t, J=9.2 Hz, 2H), 5.32 (s, 2H),5.02 (s, 2H), 2.15 (s, 3H); LC/MS C-18 column, t_(r)=2.35 minutes (5 to95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm,at 50° C.). ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0188 (M+H calcd forC₂₁H₁₆BrF₄N₂O₄ requires 515.0224).

Example 564

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde

Step 1: To a room temperature solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-dihydroxyelhyl)-6-methylpyridin-2(1H)-one(550 mg, 1.10 mmol) in toluene (10.0 mL) was added lead(IV) acetate (810mg, 1.82 mmol). The resulting dark brown solution was stirred for twohours until complete consumption of starting material by LCMS analysis.The reaction mixture was then diluted with ethyl acetate (400 mL), waterwashed (3×100 mL), and brine washed (3×300 mL). The resulting organicextract was separated, Na₂SO₄ dried, and concentrated. The resultingdark residue was subjected to SiO₂ chromatography with ethylacetate/hexanes (1:1) to furnish a light yellow solid (321 mg, 62%). ¹HNMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 7.56-7.48 (m, 2H), 7.12 (app t,J=7.3 Hz, 2H), 6.94 (app t, J=8.5 Hz, 1H), 6.88 (app t, J=8.7 Hz, 1H),5.33 (s, 2H), 2.45 (s, 3H); LC/MS C-18 column, t_(r)=2.94 minutes (5 to95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm,at 50° C.). ES-MS m/z 470 (M+H). ES-HRMS m/z 469.9996 (M+H calcd forC₂₀H₁₃BrF₄NO₃ requires 470.0009).

Example 565

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde oxime

Step 1: To a room temperature solution of5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde(316.5 mg, 0.673 mmol) in methanol (10.0 mL) was added solid NH₂OH.H₂O(300.0 mg, 4.32 mmol) and sodium acetate (480.0 mg, 5.85 mmol). Theresulting suspension was stirred for 1.5 hours until completeconsumption of starting material by LCMS analysis. The reaction mixturewas then concentrated in vacuo and the resulting residue was dilutedwith methylene chloride (300 mL) and water washed (2×100 mL). Theresulting organic extract was separated, Na₂SO₄ dried, and concentratedto furnish a light yellow solid (390 mg, 99%). ¹H NMR (400 MHz, d₄-MeOHwith CDCl₃) δ 8.06 (s, 1H), 7.51-7.40 (m, 2H), 7.06 (app dd, J=8.6, 7.4Hz, 2H), 6.88 (app dt, J=8.3, 2.4 Hz, 1H), 6.83 (app dt, J=9.2, 2.4 Hz,1H), 5.13 (s, 2H), 2.76 (s, 3H); LC/MS C-18 column, t_(r)=2.61 minutes(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0093 (M+H calcdfor C₂₀H₁₄BrF₄N₂O₃ requires 485.0118).

Example 566

5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

Step 1: To a room temperature solution of5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehydeoxime (340.0 mg, 0.701 mmol) in methylene chloride (8.0 mL) was addedsolid 1,1′ carbonyl diimidazole (290.0 mg, 1.79 mmol) and sodium acetate(480.0 mg, 5.85 mmol). The resulting solution was stirred for 1.5 hoursuntil complete consumption of starting material by LCMS analysis. Thereaction mixture was then concentrated in vacuo and the resultingresidue was directly applied to SiO₂ chromatography with ethylacetate/hexanes (3:7) to furnish a white solid (262 mg, 90%). ¹H NMR(400 MHz, CDCl₃) δ 7.61 (app q, J=7.4 Hz, 1H), 7.52 (app tt, J=8.4, 6.3Hz, 1H), 7.14 (app dd, J=8.6, 7.4 Hz, 2H), 6.94 (app dt, J=8.5, 2.5 Hz,1H), 6.88 (app dt, J=8.5, 2.4 Hz, 1H), 5.43 (s, 2H), 2.32 (s, 3H); LC/MSC-18 column, t_(r)=2.95 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). IR (neat) 3111,3067, 3032, 2914, 2840, 2215 (nitrile stretch), 1678, 1587, 1470 cm⁻¹;ES-MS m/z 467 (M+H). ES-HRMS m/z 467.0037 (M+H calcd for C₂₀H₁₂BrF₄N₂O₂requires 467.0013).

Example 567

4-(benzyloxy)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

Step 1: A solution of4-(benzyloxy)-3-bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one(1.42 g, 3.50 mmol) in 1,2 dichloroethane (18 mL) was treated with solidN-iodosuccinimide (1.59 g, 7.06 mmol) and dichloroacetic acid (0.260 g,2.01 mmol). The resulting solution was stirred and heated to 50° C. for2.5 hours until complete consumption of starting material by LCMS. Atthis time the reaction was diluted with ethyl acetate (400 mL) andwashed with sodium sulfite (5% aqueous solution, 100 mL) and brine(3×200 mL) The resulting organic extracts were Na₂SO₄ dried, filtered,and concentrated in vacuo to approximately 30 mL volume. The resultingmother liquor rapidly precipitated and furnished an amorphous solid thatwas collected and dried at 1 mm Hg vacuum to provide a solid (1.49 g,82%). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (app d, J=6.8 Hz, 2H), 7.51-7.38(m, 4H), 7.09 (app t, J=8.0 Hz, 2H), 5.20 (s, 2H), 2.39 (s, 3H); LC/MSC-18 column, t_(r)=3.28 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 532(M+H). ES-HRMS m/z 531.9196 (M+H calcd for C₁₉H₁₄BrF₂₁NO₂ requires531.9215).

Example 568

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-oxiran-2-ylpyridin-2(1H)-one

Step 1: A sample of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one(10.0 mg, 0.0214 mmol) was treated with a solution of dimethyl dioxiranein acetone (approx. 0.1 M, 5 mL, 0.5 mmol). The reaction vessel wascapped and sealed, and the resulting solution was stirred 6.0 hours. Atthis time the reaction was concentrated in vacuo and the resultingresidue was subjected to SiO₂ chromatography with ethyl acetate/hexanes(4:6) to furnish a semi-solid (5.0 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ7.57 (app q, J=7.4 Hz, 1H), 7.46 (app tt, J=8.5, 6.2, 1H), 7.11 (app t,J=8.0 Hz, 2H), 6.94 (app t, J=8.2 Hz, 1H), 6.83 (app t, J=9.2 Hz, 1H),5.31 (AB-q, J=10.9 Hz, Δ=29.0 Hz, 2H), 3.63 (app t, J=3.5 Hz, 1H), 3.03(dd, J=9.4, 5.0, 1H), 2.85 (dd, J=5.2, 2.7, 1H), 2.14 (s, 3H); LC/MSC-18 column, t_(r)=2.26 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 484(M+H) and 502 (M+H₃O). ES-HRMS m/z 502.0273 (M+H₃O calcd forC₂₁H₁₇BrF₄NO₄ requires 502.0272).

Example 569

4-(benzylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

Step 1: A slurry of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one(80.0 mg, 0.141 mmol) and benzyl amine (300 mg, 2.80 mmol) was heated to63° C. and stirred for 1.0 hours until complete disappearance ofstarting material by LCMS analysis. The reaction mixture was thendiluted with ethyl acetate (300 mL) and brine washed (3×200 ml). Theresulting organic extracts were Na₂SO₄ dried, filtered, and concentratedin vacuo to a residue that was then subjected to SiO₂ chromatographywith ethyl acetate/hexanes (3:7) to furnish a brown solid (60.0 mg,81%). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.22 (m, 6H), 7.04 (app t, J=8.4Hz, 2H), 5.02 (br t, J=1.6 Hz, 1H), 4.86 (d, J=5.5 Hz, 2H), 2.37 (s,3H); LC/MS C-18 column, t_(r)=3.02 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z531 (M+H). ES-HRMS m/z 530.9344 (M+H calcd for C₁₉H₁₅BrF₂₁N₂O requires530.9375).

Example 570

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-[(E)-2-phenylethenyl]pyridin-2(1H)-one

Step 1: To an anhydrous −78° C. solution of β-bromostyrene (1.80 g, 10.0mmol) in ether (18 mL) was added sequentially a solution of zincchloride (10.0 mL, 1.0 M ether, 10.0 mmol) over 1.0 minute and asolution of tert-butyl lithium (15.0 mL, 1.6 M pentanes, 24.0 mmol) over8.0 minutes. The resulting solution became cloudy and the reactionmixture was allowed to warm to room temperature on its own accord (over30 minutes). After an additional 1.0 hour, the suspension wastransferred by syringe directly to a separate vessel containing asolution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one(1.50 g, 2.64 mmol) and tetrakis(tripheylphosphine)palladium (294 mg,0.254 mmol) in anhydrous THF (4 mL). This resulting suspension washeated to 55° C. for 40 minutes and cooled to room temperature, wherebyit was stirred under a positive pressure of argon for an additional 4.0hours until complete disappearance of starting material by LCMSanalysis. The reaction suspension was subsequently treated with NaHCO₃and brine (100 and 200 mL, respectively). The resulting emulsion wasextracted with ethyl acetate (3×300 mL) and the organic extracts wereNa₂SO₄ dried, filtered, and concentrated in vacuo to a residue that wasthen subjected to SiO₂ chromatography with ethyl acetate/hexanes (3:7)to furnish a reddish solid (1.25 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ7.51-7.39 (m, 2H), 7.38-7.24 (m, 5H), 7.10 (app t, J=8.5 Hz, 2H), 6.84(d, J=17.2 Hz, 1H), 6.82-6.75 (m, 1H), 6.74-6.68 (m, 1H), 6.69 (d,J=17.2, 1H), 5.11 (br s, 2H), 2.15 (s, 3H); LC/MS C-18 column,t_(r)=3.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 544 (M+H). ES-HRMSm/z 544.0565 (M+H calcd for C₂₇H₁₉BrF₄NO₂ requires 544.0530).

Example 574

4-(allylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

Step 1: A slurry of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6methylpyridin-2(1H)-one (1.40 g, 2.46 mmol) and allyl amine (1.98 mg,34.6 mmol) was heated to 50° C. and stirred for 1.0 hours until completedisappearance of starting material by LCMS analysis. The reactionmixture was then concentrated in vacuo (1.0 mm Hg) for 2 days at 50° C.to furnish a brown solid (1.18 g, 99%) ¹H NMR (300 MHz, CDCl₃) δ 7.43(app tt, J=8.4, 6.2, 1H), 7.09 (app t, J=8.4 Hz, 2H), 6.02 (app dq,J=11.0, 6.2 Hz, 1H), 5.39 (dd, J=16.9, 1.8 Hz, 1H), 5.30 (dd, J=11.0,1.8 Hz, 1H), 4.84 (br s, 1H), 4.35 (br s, 2H), 2.42 (s, 3H); LC/MS C-18column, t_(r)=2.71 minutes (5 to 95% acetonitrile/water over 5 minutesat 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 481 (M+H).ES-HRMS m/z 480.9261 (M+H calcd for C₁₅H₁₃BrF₂₁N₂O requires 480.9219).

Example 575

4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

Step 1: A solution of4-(allylamino)-3-bromo-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one(1.00 g, 2.07 mmol) and tetrakis(tripheylphosphine)palladium (420 mg,0.363 mmol) in anhydrous THF (10 mL) under an argon stream was heated to64° C. and stirred for 12 hours until complete disappearance of startingmaterial by LCMS analysis. The reaction suspension was subsequentlytreated with brine (600 mL). The resulting emulsion was extracted withethyl acetate (3×400 mL) and the organic extracts were anhy. Na₂SO₄dried, filtered, and concentrated in vacuo to a residue that was thensubjected to SiO₂ chromatography with ethyl acetate/hexanes (gradient3:7) to furnish a solid (376 mg, 45%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.55(app tt, J=8.7, 6.3, 1H), 7.18 (app t, J=7.6 Hz, 2H), 5.89 (app ddd,J=15.4, 10.3, 5.1 Hz, 1H), 5.01 (app d, J=17.0, Hz, 1H), 5.50 (s, 1H),5.22 (app d, J=11.0 Hz, 1H), 4.35 (app d, J=5.0 Hz, 2H), 2.36 (s, 3H);LC/MS C-18 column, t_(r)=2.33 minutes (5 to 95% acetonitrile/water over5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 403(M+H). ES-HRMS m/z 403.0133 (M+H calcd for C₁₅H₁₄F₂₁N₂O requires403.0113).

Example 576

4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one

Step 1: A solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one(197 mg, 0.445 mmol) and allyl amine (1.32 mg, 23.1 mmol) in THF (6.0mL) was heated to 68° C. and stirred for 74.0 hours. The reactionmixture was then concentrated in vacuo (30 mm Hg) to furnish a residuethat was subjected to SiO₂ chromatography with ethyl acetate/hexanes(3:7) to furnish a solid (36.0 mg, 23%). ¹H NMR (400 MHz, d₄-MeOH) δ7.55 (app tt, J=8.5, 6.5, 1H), 7.18 (app t, J=8.5 Hz, 2H), 6.14 (s, 1H),5.91 (app dq, J=11.5, 6.4 Hz, 1H), 5.23 (dd, J=17.0, 1.5 Hz, 1H), 5.19(dd, J=11.0, 1.6 Hz, 1H), 4.00 (app d, J=4.7 Hz, 2H), 1.98 (s, 3H);LC/MS C-18 column, t_(r)=2-0.24 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z355 (M+H). ES-HRMS m/z 355.0257 (M+H calcd for C₁₅H₁₄F₂BrF₂N₂O requires355.0252).

Example 577

ethyl3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-1,2′-bipyridine-5′-carboxylate

Step 1: To a room temperature suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (500.0 mg,1.51 mmol) and Cs₂CO₃ (1.50 g, 4.60 mmol) in 1-methyl-2-pyrrolidinone(3.0 mL) was added ethyl 6-chloronicotinate (900 mg, 4.85 mmol). Theresulting suspension was stirred and heated to 106° C. for 36 hoursuntil complete consumption of starting material by LCMS analysis. Thereaction mixture was then diluted with ethyl acetate (400 mL), waterwashed (3×200 mL). The resulting organic extract was separated, Na₂SO₄dried, and concentrated. The resulting dark residue was subjected toSiO₂ chromatography with ethyl acetate/hexanes (3:7) to furnish a solid.¹H NMR (400 MHz, d₄-MeOH) δ 8.68 (app d, J=2.5 Hz, 1H), 8.39 (dd, J=8.7,2.3 Hz, 1H), 7.62 (app q, J=8.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.08(s, 1H), 7.08-6.99 (m, 2H), 5.31 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 2.43(s, 3H), 1.37 (t, J=7.1 Hz, 3H); LC/MS C-18 column, t_(r)=3.44 minutes(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 479 (M+H) ES-HRMS m/z 479.0401 (M+H calcdfor C₂₁H₁₈BrF₂N₂O₄ requires 479.0431).

Example 578

3-bromo-4-[(2,4-difluorobenzyl)oxy]-5′-(1-hydroxy-1-methylethyl)-6-methyl-2H-1,2′-bipyridin-2-one

Step 1: To a 0° C. solution of methyl magnesium bromide (3.0 M, 3.5 mL,10.5 mmol) was added dropwise over 15 minutes a solution of ethyl3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2oxo-2H-1,2′-bipyridine-5′-carboxylate (500.0 mg, 1.05 mmol) in THF (4.0mL). The internal temperature of the reaction was never allowed toexceed 0° C. The resulting solution was maintained for 30 minutes untilcomplete consumption of starting material by LCMS analysis. Next, asolution of ammonium chloride (saturated aqueous, 160 mL) was added. Thereaction mixture was extracted with ethyl acetate (3×100 mL) and theresulting organic extracts were separated, Na₂SO₄ dried, andconcentrated in vacuo to a residue that was subjected to SiO₂chromatography with ethyl acetate/hexanes (gradient 3:7 to 6:4) tofurnish a solid (386 mg, 79%). ¹H NMR (400 MHz, d₄-MeOH) δ 8.23 (app d,J=2.8 Hz, 1H), 7.97 (dd, J=8.6, 2.3 Hz, 1H), 7.61 (app q, J=8.2 Hz, 1H),7.06-7.00 (m, 3H), 7.00 (s, 1H), 5.30 (s, 2H), 2.38 (s, 3H), 1.54 (s,6H); LC/MS C-18 column, t_(r)=2.75 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z465 (M+H). ES-HRMS m/z 465.0615 (M+H calcd for C₂₁H₂₀BrF₂N₂O₃ requires465.0620). IR(neat) 3366, 3030, 2974, 1600, 1507, 1362, 1232 cm⁻¹. ¹³CNMR (400 MHz, d₄-MeOH, visible peaks with carbon fluorine couplingpresent) δ 164.4, 160.7, 158.9, 157.6, 143.6, 141.6, 137.5, 131.61,131.56, 131.51, 131.46, 119.29, 119.25, 119.15, 119.11, 112.23, 111.55,111.52, 111.33, 111.29, 106.0, 103.9, 103.7, 103.4, 96.8, 70.3, 64.9,64.8, 30.5, 22.6.

Example 579

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-furylmethyl)-6-methylpyridin-2(1H)-one

Step 1: Preparation of the title compound. To a room temperaturesuspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.0 mg,1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added2-(chloromethyl)furan (461 mg, 3.97 mmol). The resulting suspension wasstirred and heated to 68° C. for 9 hours until complete consumption ofstarting material by LCMS analysis. The reaction mixture was thendiluted with ethyl acetate (400 mL), water washed (3×200 mL). Theresulting organic extract was separated, Na₂SO₄ dried, and concentrated.The resulting dark residue was subjected to SiO₂ chromatography withethyl acetate/hexanes (4:6) to furnish a solid. ¹H NMR (300 MHz,d₄-MeOH) δ 7.62 (app q, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.06 (app t, J=8.7Hz, 2H), 6.51 (s, 1H), 6.41-6.37 (m, 2H), 5.37 (s, 2H), 5.32 (s, 2H),2.61 (s, 3H); LC/MS C-18 column, t_(r)32 2.63 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 410 (M+H). ES-HRMS m/z 410.0177 (M+H calcd forC₁₈H₁₅BrF₂NO₃ requires 410.0198).

Example 580

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(thien-2-ylmethyl)pyridin-2(1H)-one

Step 1: To a room temperature suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.0 mg,1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added2-(chloromethyl)thiophene (461 mg, 3.97 mmol). The resulting suspensionwas stirred and heated to 68° C. for 12 hours until complete consumptionof starting material by LCMS analysis. The reaction mixture was thendiluted with ethyl acetate (400 mL), water washed (3×200 mL). Theresulting organic extract was separated, Na₂SO₄ dried, and concentrated.The resulting dark residue was subjected to SiO₂ chromatography withethyl acetate/hexanes (4:6) to furnish a solid. ¹H NMR (400 MHz,d₄-MeOH) δ 7.58 (app q, J=8.2 Hz, 1H), 7.30 (app dd, J=5.1, 1.2 Hz, 1H),7.05 (d, J=2.6 Hz, 1H), 7.01 (app t, J=8.1 Hz, 2H), 6.93 (dd, J=5.1, 3.4Hz, 1H), 6.43 (s, 1H), 5.49 (s, 2H), 5.25 (s, 2H), 2.51 (s, 3H); LC/MSC-18 column, t_(r)=2.74 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 426(M+H). ES-HRMS m/z 425.9936 (M+H calcd for C₁₈H₁₅BrF₂NO₂S requires425.9969).

Example 581

3-bromo-1-(2,6-difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(1H)-one

Step 1: To a suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one(250 mg, 0.445 mmol) and furfuryl alcohol (198 mg, 2.0 mmol) in THF (2.5mL) was added solid NaH (46.0 mg, 1.92 mmol). Following the evolution ofgas, the resulting suspension laws heated to 60° C. and stirred for 3.5hours until complete consumption of starting material by LCMS analysis.The reaction mixture was then diluted with ammonium chloride (saturatedaqueous, 100 mL) and extracted with ethyl acetate (3×100 mL). Theresulting organic extracts were separated, Na₂SO₄ dried, andconcentrated to provide a residue that was subjected to SiO₂chromatography with ethyl acetate/hexanes (3:7) to furnish a solid(110.0 mg, 49%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.63 (app tt, J=8.5, 6.2,1H), 7.62-7.61 (m, 1H), 7.28 (app t, J=8.5 Hz, 2H), 6.77 (s, 1H), 6.68(d, J=4.1 Hz, 1H), 6.51 (dd, J=4.2, 3.9 Hz, 1H), 5.34 (s, 2H), 2.15 (s,3H); LC/MS C-18 column, t_(r)=2.43 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z396 (M+H). ES-HRMS m/z 396.0044 (M+H calcd for C₁₇H₁₃BrF₂NO₃ requires396.0041).

Example 582

3-bromo-1-[2-fluoro-6-(3-furylmethoxy)phenyl]-4-(3-furylmethoxy)-6-methylpyridin-2(1H)-one

By following the method of preparation of3-bromo-1-(2,6-difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(1H)-one(Example 581) and substituting 3-furylmethanol for furfuryl alcohol, thetitle compound was prepared in 55% chemical yield. ¹H NMR (400 MHz,d₄-MeOH) δ 7.64 (s, 1H), 7.55-7.42 (m, 3H), 7.40 (app t, J=1.4 Hz, 1H),7.12 (d, J=9.0 Hz, 1H), 6.92 (app t, J=8.4 Hz, 1H), 6.58 (s, 2H), 6.34(br s, 1H), 5.21 (s, 2H), 5.03 (AB-q, J=14.0 Hz, Δ=58.0 Hz, 2H), 1.99(s, 3H); LC/MS C-18 column, t_(r)=2.67 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 474 (M+H). ES-HRMS m/z 474.0346 (M+H calcd forC₂₂H₁₈BrFNO₅ requires 474.0347).

Example 583

3-bromo-1-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-(thien3-ylmethoxy)pyridin-2(1H)-one

By following the method of preparation of3-bromo-1-(2,6-difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(1H)-oneExample 581 and substituting thien-3-ylmethanol for furfuryl alcohol,the title compound was prepared in 38% chemical yield. ¹H NMR (400 MHz,d₄-MeOH) δ 7.50-7.42 (m, 3H), 7.33 (dd, J=5.0, 3.0 Hz, 1H), 7.26 (br d,J=2.0 Hz, 1H), 7.19 (dd, J=5.0, 1.2 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H),6.98 (dd, J=14.9, 1.3 Hz, 1H), 6.93 (dt, J=8.7, 1.0 Hz, 1H), 6.53 (br s,1H), 5.33 (s, 2H), 5.14 (AB-q, J=12.1 Hz, Δ=50.0 Hz, 2H), 1.97 (s, 3H);LC/MS C-18 column, t_(r)=2.93 minutes (5 to 95% acetonitrile/water over5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 506(M+H). ES-HRMS m/z 505.9881 (M+H calcd for C₂₂H₁₈BrFNO₃S₂ requires505.9890).

Example 584

methyl2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoateStep 1: Preparation of3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-(methoxycarbonyl)benzoicacid

4-Hydroxy-6-methyl-2-pyrone (75.0 g, 595 mmol) and3-amino-4-(methoxycarbonyl)benzoic acid (40.0 g, 0.205 mmol) weresuspended in 56 ml of 1,2-dichlorobenzene in a 500 ml, 3-necked, roundbottom flask equipped with a J-Kem temperature controller probe, aDean-Stark trap, and a heating mantle. The reaction was heated to 180°C. over a period of 26 minutes during which time all solids dissolved.Upon reaching an internal temperature of 180° C., the reaction wasallowed to maintain this temperature for an additional 25.0 minutesduring which time the evolution of water from the reaction mixture wasevident. Next, the heating apparatus was removed and the reaction wasallowed to cool on its own accord to about 100° C. The reaction was thendiluted with 160 ml of toluene and stirred. After about 10 minutes, thereaction reached room temperature and a gummy solid had formed. Theprecipitate was filtered, washed with EtOAc (400 mL) and water (200 mL,55° C.), and dried in vacuo to give a tan solid (30.5 g, 49%). ¹H NMR(400 MHz, d₄-MeOH) δ 8.20-8.09 (m, 2H), 7.84 (s, 1H), 6.08 (app d, J=1.0Hz, 1H), 5.76 (app d, J=2.3 Hz, 1H), 3.76 (s, 3H), 1.91 (s, 3H). LC/MS,C-18 column, t_(r)=1.96 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 304(M+H). ES-HRMS m/z 304.0803 (M+H calcd for C₁₅H₁₄NO₆ requires 304.0816).

Step 2: Preparation of methyl2-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate

To a solution of3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-(methoxycarbonyl)benzoicacid (from Step 1) (1.00 g, 3.30 mmol) in dimethylformamide (10 mL) andTHF (10 mL) was added cyclohexylcarbodiimide-derivatized silica gel (aproduct of Silicycle chemical division Quebec, Canada) with a loading of0.60 mmol/g (15.2 g, 9.73 mmol). After stirring for 30 minutes, asolution of methylamine (2.0 M, THF, 2.9 mL, 5.8 mmol) was addedfollowed by the addition of 1-hydroxy-benzotriazole (20.0 mg, 0.15mmol). The reaction suspension was allowed to stir for 24 hours untilthe complete disappearance of starting material by LCMS analysis. Thesilica suspension was filtered and washed with 300 mL ethylacetate/methanol (9:1) and 300 mL ethyl acetate/methanol (1:1). Theresulting mother liquor was concentrated to furnish a brown semi-solid(898 mg, 86%). ¹H NMR (300 MHz, d₄-MeOH) δ 8.22 (d, J=8.0 Hz, 1H), 8.04(dd, J=8.3, 1.9 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 6.13 (d, J=1.5, Hz,1H), 5.80 (d, J=2.2 Hz, 1H), 3.80 (s, 3H), 3.03 (s, 3H), 1.97 (s, 3H).LC/MS, C-18 column, t_(r)=1.31 minutes (5 to 95% acetonitrile/water over5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 317(M+H). ES-HRMS m/z 317.1142 (M+H calcd for C₁₆H₁₇N₂O₅ requires317.1132).

Step 3: Preparation of methyl2-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate

To a room temperature suspension of methyl2-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate(from Step 2) (406.0 mg, 1.28 mmol) in CH₂Cl₂ (8 mL) was added solidN-bromosuccinimide (251 mg, 1.41 mmol) and stirred for 10 minutes untilcomplete consumption of starting material by LCMS analysis. The reactionwas next diluted with CH₂Cl₂ (5 mL), ethyl acetate (5 mL), and hexanes(1 mL). After approximately 30 minutes the resulting white precipitatewas filtered and washed with ethyl acetate (5 mL) to furnish a solid(298 mg, 62%). ¹H NMR (400 MHz, d₄-MeOH) δ 8.20 (d, J=8.2 Hz, 1H), 8.01(d, J=8.1 Hz, 1H), 7.69 (s, 1H), 6.18 (s 1H), 3.75 (s, 3H), 2.91 (s,3H), 1.91 (s, 3H); LC/MS, t_(r)=1.27 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 395 (M+H). ES-HRMS m/z 395.0237 (M+H calcd forC₁₆H₁₆BrN₂O₅ requires 395.0237).

Step 4: Preparation of the Title Compound

To a solution of methyl2-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate(from Step 3) (241 mg, 0.610 mmol) in dimethylformamide (0.5 mL) wasadded sequentially K₂CO₃ (240 my, 1.73 mmol) and 2,4 difluorobenzylbromide (0.085 mL, 0.66 mmol). The resulting suspension was stirred for6.5 hours until complete consumption of starting material by LCMSanalysis. The reaction was then diluted with ethyl acetate (200 mL) andbrine washed (3×200 mL). The resulting organic extract was Na₂SO₄ dried,filtered, and concentrated in vacuo to approximately 5 mL volume. Theresulting mother liquor rapidly precipitated and furnished an amorphoussolid that was collected. ¹H NMR (400 MHz, d₄-MeOH) δ 8.22 (d, J=8.2 Hz,1H), 8.03 (dd, J=8.2, 1.7 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.67 (app q,J=8.3 Hz, 1H), 7.05 (app t, J=8.6 Hz, 2H), 6.64 (s, 1H), 5.37 (s, 2H),3.74 (s, 3H), 2.90 (s, 3H), 2.01 (s, 3H) LC/MS C-18 column, t_(r)=2.87minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 521 (M+H). ES-HRMS m/z 521.0491(M+H calcd for C₂₃H₂₀BrF₂N₂O₅ requires 521.0518).

Example 585

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-(1-hydroxy-1-methylethyl)-N-methylbenzamide

Step 1: To a −10° C. solution of methyl magnesium bromide (3.0 M, 0.60mL, 1.8 mmol) was added dropwise over 10 minutes a solution of methyl2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate(85.0 mg, 0.163 mmol) in THF (1.0 mL). The internal temperature of thereaction was never allowed to exceed 0° C. The resulting solution wasmaintained for 10 minutes. Next, a solution of ammonium chloride(saturated aqueous, 100 mL) was added. The reaction mixture was removedfrom the bath and resulting emulsion was extracted with ethyl acetate(3×100 mL) and the resulting organic extracts were separated, Na₂SO₄dried, and concentrated in vacuo to a residue that was subjected to SiO₂chromatography with ethyl acetate/hexanes (gradient 3:7 to 6:4) tofurnish a solid (16 mg, 19%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.89 (d, J=8.5Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.61 (app q, J=8.2 Hz, 1H), 7.41 (s,1H), 7.03-6.99 (m, 2H), 6.57 (s, 1H), 5.30 (s, 2H), 2.83 (s, 3H), 2.05(s, 3H), 1.51 (s, 3H), 1.39 (s, 3H); LC/MS C-18 column, t_(r)=2.28minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 521 (M+H). ES-HRMS m/z 521.0860(M+H calcd for C₂₄H₂₄BrF₂N₂O₄ requires 521.0882).

Example 586

3-bromo-1-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-(thien-3-ylmethoxy)pyridin-2(1H)-one

By following the method of preparation of3-bromo-1-(2,6-difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(1H)-oneExample 581 and substituting4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamidefor3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one,the title compound was prepared in 76% chemical yield. ¹H NMR (400 MHz,d₄-MeOH) δ 7.83 (d, J=8.1 Hz, 2H), 7.54 (app d, J=1.1 Hz, 1H), 7.19 (d,J=8.1 Hz, 2H), 6.57 (d, J=3.2 Hz, 1H), 6.53 (s, 1H), 6.43 (dd, J=3.1,1.8 Hz, 1H), 5.45 (br s, 2H), 5.22 (s, 2H), 2.34 (s, 3H); LC/MS C-18column, t_(r)=1.98 minutes (5 to 95% acetonitrile/water over 5 minutesat 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 417 (M+H).ES-HRMS m/z 417.0469 (M+H calcd for C₁₉H₁₈BrN₂O₄ requires 417.0444).

Example 587

(−)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide

Example 489 (1.78 g, 4.36 mmol) were separated using a ChiralTechnologies Chiralpak AD column (21 mm×250 mm, 20 μm) eluting with 100%ethanol (isocratic, 20 ml/min), loading 10 mg per injection. Fractionsof the early-eluting atropisomer were pooled and concentrated in vacuoto the title compound (718 mg, 80%). Analytical chiral LC (Chiralpak AD,4.6 mm×50 mm, 10 μm particle size, 0.5 ml/min ethanol) Retention time:1.70 min, ee 94%. [α]_(D)=−23.8° (5 mg/ml DMSO, 22° C.) ¹H NMR (400 MHz,DMSO-d₆) δ 8.42 (br qr, J=4.51 Hz, 1H), 7.82 (dd, J=7.92, 1.70 Hz, 1H),7.68 (dt, J=8.24, 6.58 Hz, 1H), 7.58 (d, J=1.59 Hz, 1H), 7.48 (d, J=7.98Hz, 1H), 7.34 (dt, J=9.90, 2.50 Hz, 1H), 7.18 (dt, J=8.53, 2.57 Hz, 1H),6.71 (s, 1H), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H), 1.88 (s, 3H).¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.58 (quintet, J=7.49 Hz, 1F), −113.65(quartet, J=9.11 Hz, 1F). ES-HRMS m/z 477.0612 (M+H calcd forC₂₂H₂₀BrF₂N₂O₃ requires 477.0620).

Example 588

(+)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide

The title compound was prepared as in Example 587 pooling thelate-eluting atropisomer (722 mg, 81%). Analytical chiral LC (ChiralpakAD, 4.6 mm×50 mm, 10 μm particle size, 0.5 ml/min ethanol) Retentiontime: 2.00 min, ee 98%. [α]_(D)=+28.20 (5 mg/ml DMSO, 22° C.). ¹H NMR(400 MHz, DMSO-d₆) δ 8.42 (br qr, J=4.51 Hz, 1H), 7.82 (dd, J=7.92, 1.70Hz, 1H), 7.68 (dt, J=8.24, 6.58 Hz, 1H), 7.58 (d, J=1.59 Hz, 1H), 7.48(d, J=7.98 Hz, 1H), 7.34 (dt, J=9.90, 2.50 Hz, 1H), 7.18 (dt, J=8.53,2.57 Hz, 1H), 6.71 (s, 1H), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H),1.88 (s, 3H). ¹⁹F-NMR (400 MHz, DMSO-d₆) δ −109.58 (quintet, J=7.49 Hz,1F), −113.65 (quartet, J=9.11 Hz, 1F). ES-HRMS m/z 477.0614 (M+H calcdfor C₂₂H₂₀BrF₂N₂O₃ requires 477.0620).

Example 589

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzamideStep 1: Preparation of methyl3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

4-Hydroxy 6-methyl-2-pyrone (24.5 g, 193.9 mmol) andmethyl-3-amino-2-chlorobenzoate (30 g, 161.6 mmol) were suspended in 75ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flaskequipped with a J-Kem temperature controller probe, a Dean-Stark trap,and a heating mantle. The reaction was heated to 175° C. for 20 minutes,during which, water and some 1,2-dichlorobenzene was collected in theDean-Stark trap. The reaction was allowed to cool to about 110° C. Atthis point, 200 ml of toluene was added. The toluene mixture was allowedto stir for 72 hours at room temperature. A precipitate was collected ona filter pad. The precipitate was filtered and washed 3 times withtoluene, 3 times with 50° C. water to remove excess pyrone, and dried invacuo to give a tan solid (13.0 g, 27% yield). ¹H NMR (300 MHz, CD₃OD) δ8.26 (d, J=1.81 Hz, 1H), 8.14 (dd, J=8.26, 1.81 Hz, 1H), 7.54 (d,J=8.26, Hz, 1H), 6.14 (dd, J=2.42, 1.0 Hz, 1H), 5.83 (d, J=2.42 1H),4.00 (s, 3H), 1.96 (s, 3H); LC/MS, t_(r)=1.81 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES MS m/z 294 (M+H).

Step 2: Preparation of methyl3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate(from Step 1) (2.4 g, 8.17 mmol) was taken up in DMF (10 ml).2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K₂CO₃ (1.13 g, 8.17mmol) were added. The reaction stirred for 6 hours at room temperature.At this time, the reaction was poured into water (200 ml) and extractedwith ethyl acetate. The ethyl acetate layer was dried over Na₂SO₄,filtered, and the solvent removed in vacuo to give amber oil (2.62 g,77% crude yield). LC/MS, t_(r)=2.79 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z294 (M+H).

Step 3: Preparation of methyl4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate

Methyl3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(from step 2) (2.60 g, 6.21 mmol) was taken up in CH₂Cl₂ (20 ml).N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture stirredat room temperature for 4 hours. The CH₂Cl₂ is removed in vacuo and theresidue is taken up in CH₃CN. The resulting precipitate is collected ona filter pad and washed with CH₃CN to yield a white solid (0.75 g, 24%).¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=1.88 Hz, 1H), 8.06 (dd, J=8.19,1.75 Hz, 1H), 7.59 (app q, J=8.46 Hz, 1H), 7.33 (d, J=8.19, 1H), 6.96(dt, J=8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s,2H), 3.95 (s, 3H), 1.95 (s, 3H); ES-MS m/z 478 (M+H). ES-HRMS m/z497.9892 (M+H calcd for C₂₂H₁₆BrClF₂NO₄ requires 497.9914).

Step 4: Preparation of4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoicacid

Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate(2.30 g, 4.61 mmol) was taken up in THF (20 ml) and H₂O (4 ml). 2.5 NNAOH (9.2 ml) was added to the vessel and the reaction stirred overnightto completion. Concentrated HCl was added dropwise until reaction wasmade acidic (pH=1). H₂O (100 ml) and THF (100 ml) were added to themixture. The contents were poured into a separatory funnel and theaqueous layer was extracted with ethyl acetate. The organic layer wasdried over Na₂SO₄, the solvent removed in vacuo, and the residue wastaken up in a 50% mixture of ethyl acetate/hexane. The precipitate wascollected on a filter pad to yield a white powder (1.5 g, 67%). ¹H NMR(300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J=1.81 Hz, 1H), 8.06 (dd, J=6.24,1.81 Hz, 1H), 7.73 (app q, J=8.46, 1H), 7.68 (d, J=8.26 Hz, 1H), 7.38(dt, J=9.48, 2.62 Hz, 1H) 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H),3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749(M+H calcd for C₂₀H₁₄BrClF₂NO₄ requires 483.9757).

Step 5:4-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoicacid (0.5 g, 1.03 mmol) was taken up in THF (10 ml).2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.22 g, 1.24 mmol) and N-methylmorpholine (0.34 ml, 3.09 mmol) were added. The mixture stirred at roomtemperature for 1 hour. At this time, NH₄OH (2.5 ml) was added and thereaction stirred at room temperature for one more hour. To the reactionmixture was added more THF (50 ml) and water (200 ml). The mixture wasextracted with ethyl acetate. The ethyl acetate extraction was washedwith saturated brine solution. The brine layer was extracted with ethylacetate. The organic layers were combined, dried over Na₂SO₄, filteredand the solvent was removed in vacuo. The residue was taken up in ethylacetate and the resulting precipitate was collected on a filter pad toyield a white powder (0.38 g, 76%) ¹H NMR (300 MHz, CD₃OD) δ 8.18 (d,J=1.81 Hz, 1H), 8.02 (dd, J=8.26, 2.01 Hz, 1H), 7.69 (app q, J=8.26 Hz,1H), 7.55 (d, J=8.06 Hz, 1H) 7.12-7.06 (m, 2H), 6.71 (s, 1H), 5.40 (s,2H), 2.07 (s, 3H). ES MS m/z 482 (M+H). ES-HRMS m/z 482.9919 (M+H calcdfor C₂₀H₁₅BrClF₂N₂O₃ requires 482.9917).

Example 590

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl2-oxopyridin-1(H)-yl]-4-methylbenzamide Step 1: Preparation of3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (from above) (7.5 g, 19.4 mmol) and NCS (2.6 g, 19.4 mmol) weretaken up in 65° C. dichloroethane (100 ml). A catalytic amount ofdichloroacetic acid (2 drops) was added. After two hours the solvent wasremoved in vacuo and the residue was taken up in diethyl ether. Theprecipitate was collected on a filter pad and then taken up in 50% ethylacetate/hexanes to remove residual succinimide. The precipitate wascollected on a filter pad and then dried in vacuo to produce a whitepowder (4.2 g, 52%). ¹H NMR (300 MHz, CD₃OD) δ 8.10 (dd, J=7.85) 1.81Hz, 1H), 7.83 (d, J=8.26, 1.81 Hz, 1H), 7.40 (app q, J=8.26 Hz, 1H),7.58 (d, J=7.85 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H),2.14 (s, 3H), 2.04 (s, 3H); ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0786(M+H calcd for C₂₁H₁₇ClF₂NO₄ requires 420.0809).

Step 2:3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (1.5 g, 3.57 mmol) was taken up in THF (30 ml).2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.75 g, 4.28 mmol) and N-methylmorpholine (1.18 ml, 10.72 mmol) were added. The mixture stirred at roomtemperature for 1 hour. At this time, NH₄OH (7.5 ml) was added and thereaction stirred at room temperature for one more hour. To the reactionmixture was added more THF (100 ml) and water (150 ml). The mixture wasextracted with ethyl acetate. The ethyl acetate extraction was washedwith saturated brine solution. The brine layer was extracted with ethylacetate. The organic layers were combined, dried over Na₂SO₄, filteredand the solvent was removed in vacuo. The residue was taken up in ethylacetate and the resulting precipitate was collected on a filter pad toyield a white powder (1.32 g, 88%) ¹H NMR (300 MHz, CD₃OD) δ 7.96 (dd,J=7.85, 1.81 Hz, 1H), 7.71 (d, J=1.81 Hz, 1H), 7.67 (app q, J=8.06 Hz,1H), 7.56 (d, J=8.06 Hz, 1H), 7.12-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s,2H), 2.13 (s, 3H) 2.05 (s, 3H). ES-MS m/z 419 (M+H). ES-HRMS m/z419.0979 (M+H calcd for C₂₁H₁₈ClF₂N₂O₃ requires 419.0969).

Example 591

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide

The title compound was prepared from3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (from step 1 above) (1.5 g, 3.57 mmol) in dichloromethane (35 ml).To this mixture, 2.0 M methyl amine in THF (3.6 ml, 7.14 mmol) wasadded, followed, in order, by EDCI (0.67 g, 4.28 mmol),1-hydroxybenzotriazole (0.58 g, 4.28 mmol) and triethylamine (0.99 ml,7.14 mmol). The reaction was stirred at room temperature overnight. Thereaction was quenched with NH₄Cl and extracted 3 times with ethylacetate. The combined organic layer was then washed with saturatedNaHCO₃ (aq.) and extracted 3 times with ethyl acetate. The organiclayers were combined and washed with H₂O and extracted 3 times withethyl acetate. The organic layers were combined and dried over Na₂SO₄and evaporated. The resulting residue was triturated with diethylether/hexane to obtain a solid, which was dried in vacuo to give a whitesolid (1.5 g, 72%). ¹H NMR (300 MHz, CD₃OD) δ 7.90 (dd, J=8.06, 1.81 Hz,1H), 7.67 (app q, J=6.44 Hz, 1H), 7.55 (d, J=8.06 Hz, 1H), 7.13-7.06 (m,2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.93 (s, 3H), 2.13 (s, 3H), 2.04 (s,3H); ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1153 (M+H calcd forC₂₂H₂₀ClF₂N₂O₃ requires 433.1125).

Example 592

N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzyl}propanamide

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4-0 mL).After stirring at 25° C. for 5 min the reaction was completed by LC-MS.The reaction mixture was poured into a saturated aqueous NH₄Cl solution.The aqueous mixture was extracted with ethyl acetate. The organic phasewas dried with Na₂SO₄ and concentrated in vacuo to obtain (240 mg, 91%)as a yellow solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.3 (t, J=5.8 Hz, 1H),7.6 (q, J=8.7 and 6.58 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.3 (dd, J=2.6and 7.6 Hz, 1H), 7.22 (d, J=7.51 Hz, 1H), 7.12 (td, J=2.0 and 6.5 Hz,1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J=3.6 Hz, 2H), 2.1 (q, J=7.7 Hz2H), 1.98 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+Hcalcd for C₂₃H₂₁ClF₃N₂O₃ requires 465.1187).

Example 593

N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzyl}dimethylurea

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride (250 mg, 0.56 mmol), dimethylcarbamyl chloride (52 μL,0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0mL). After stirring at 25° C. for 5 min the reaction was completed byLC-MS. The reaction mixture was poured into a saturated aqueous NH₄Clsolution. The aqueous mixture was extracted with ethyl acetate. Theorganic phase was dried with Na₂SO₄ and concentrated in vacuo to obtainthe desired product (245 mg, 86%) as a white solid. ¹H NMR (400 MHz,(CD₃OD) δ 7.61 (q, J=7.9 and 6.7 Hz, 1H), 7.4 (m, 1H), 7.3 (d, J=9.3 Hz,1H), 7.21 (m, 1H), 7.1 (m, 2H), 6.65 (s, 1H), 5.35 (s, 2H), 4.38 (s,2H), 2.9 (s, 6H), 2.1 (s, 3H) ppm. ES-HRMS m/z 480.1269 (M+H calcd forC₂₃H₂₂ClF₃N₃O₃ requires 480.1296)

Example 594

N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzyl}-2-hydroxyacetamide

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride (250 mg, 0.56 mmol), acetoxyacetyl chloride (66 μL, 0.62mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL).After stirring at 25° C. for 5 min the reaction was completed by LC-MS.NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0 mL) was added and stirredfor 10 min to give the title compound. The reaction mixture wasacidified with concentrated HCl and extracted with ethyl. The organicphase was dried with Na₂SO₄ and concentrated in vacuo to obtain (217 mg,78%) of the desired product as a yellow solid. ¹H NMR (400 MHz, (CD₃OD)δ 7.6 (q, J=7.6 and 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 7.22 (m,2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (s, 2H), 2.05 (s, 3H)ppm. ES-HRMS m/z 467.0957 (M+H calcd for C₂₂H₁₉ClF₃N₂O₄ requires467.0980).

Example 595

N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzyl}-2-hydroxy-2-methylpropanamide

The title compound was prepared essentially as described in Example 594,with 1-chlorocarbonyl-1-methylethyl acetate substituting acetoxyacetylchloride ¹H NMR (400 MHz, (CDCl₃) δ 9.9 (q, J=8.2 and 6.5 Hz, 1H), 9.7(t, J=2.6 Hz, 1H), 9.5 (t, J=8.9 Hz, 2H), 9.3 (m, 1H), 9.2 (m, 1H), 8.6(s, 1H) 7.6 (s, 2H), 6.8 (d, J=15 Hz, 1H), 6.63 (d, J=15 Hz, 1H), 4.42(d, J=3.2 Hz, 6H), 3.99 (s, 3H) ppm. ES-HRMS m/z 495.1271 (M+H calcd forC₂₄H₂₃ClF₃N₂O₄ requires 495.1293).

Example 596

N¹-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzyl}glycinamidehydrochloride

A 25 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. Themixture was cooled to 0° C. and isboutylchloroformate (77.5 μL, 0.6mmol) was added and stirred for 20 min.1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 h. Aftercompletion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL ofmethanol was added to remove the boc group. The reaction was stirred for24 h, neutralized with 2M NaOH and extracted with ethyl acetate. Theorganic phase was dried with Na₂SO₄ and concentrated in vacuo to obtain(196 mg, 66%) of the desired product as a the HCl salt. ¹H NMR (400 MHz,(CD₃OD) δ 7.6 (q, J=8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m,2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.4 (q, J=15 and 13.6 Hz, 2H), 3.7 (s,2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 466.1157 (M+H calcd forC₂₂H₂₀ClF₃N₃O₃ requires 466.1140).

Example 597

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzamide

A 250 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (3.65 g, 7.8 mmol), 4-methylmorpholine (2.6 mL, 23.4 mmol),2-chloro-4,6-dimethoxy-1,3,5-triazine (1.64 g, 9.36 mmol) andtetrahydrofuran (40 mL). After stirring the mixture for 30 min at 25°C., NH₄OH (20.0 mL) was added. The mixture was stirred for 30 min anddiluted with water. The product precipitated from solution. Theprecipitated was filtered and washed with water and diethyl ether togive the title compound (2.37 g, 65%) as a white solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 7.9 (d, J=7.3 Hz, 1H), 7.61 (q, J=8.6 and 6.7 Hz, 1H), 7.5(m, 2H), 7.3 (t, J=9.6 Hz, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.7 (s, 1H),5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 469.0172 (M+H calcd forC₂₀H₁₅BrF₃N₂O₃ requires 469.0195).

Example 598

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-methylbenzamide

A solution of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine(0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at−10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2M in THF) was added and the reaction mixture was warmed to roomtemperature as it stirred for 18 hours. The reaction mixture wasconcentrated in vacuo, suspended in water, filtered and washed withwater, ethyl acetate and diethyl ether. ¹H NMR (400 MHz, CD₃OD) δ 8.03(dddd, J=3.0, 6.4, 9.2 and 11.6 Hz, 1H), 7.81 (dd, J=3.0 and (0.2 Hz,1H), 7.66 (q, J=10.4 Hz, 1H), 7.47 (t, J=12 Hz, 1H), 7.06 (t, J=12 Hz,2H), 6.67 (s, 1H), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm. ¹⁹F NMR(400 MHz, CD₃OD) δ −111.50 (1F), −115.97 (1F), −120.16 ppm. ES-HRMS m/z481.0346 (M+H calcd for C₂₁H₁₇BrF₃N₂O₃ requires 481.0369).

Example 599

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N,N-dimethylbenzamide

A solution of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine(0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at−10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2M in THF) was added and the reaction mixture was warmed to roomtemperature as it stirred for 18 hours. The reaction mixture wasconcentrated in vacuo and partitioned between water and ethyl acetate.The organic layer was washed with brine and concentrated in vacuo. Thesolid was chromatographed on silica (95:5 methylene chloride:isopropylalcohol) to give the desired product as a white powder (0.31 g, 30%). ¹HNMR (400 MHz, CD₃OD) δ 7.64 (m, 1H), 7.50 (dd, J=2.4 and 7.2 Hz, 1H),7.45 (t, J=9.6 Hz, 1H), 7.04 (t, J=9.2 Hz, 2H), 6.65 (s, 1H), 5.36 (s,2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −111.51 (1F), −115.88 (1F), −121.90 (1F) ppm. ES-HRMS m/z495.0508 (M+H calcd for C₂₂H₁₉BrF₃N₂O₃ requires 495.0526).

Example 600

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2-fluoro-5-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-6-methylpyridin-2(1H)-oneStep 1 Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2-fluoro-5-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-6-methylpyridin-2(1H)-one

To a reaction vessel (borosilicate culture tube) was added3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoicacid (0.300 g, 0.623 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.45mmol). N,N-Dimethylformamide (3 mL) was added to the reaction vesselfollowed by approximately 1.1 g of the polymer bound carbodiimide resin(1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added tothe reaction vessel. The parallel reaction apparatus was then orbitallyshaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM atroom temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was thenadded to the reaction vessel and the reaction apparatus was orbitallyshaken at room temperature overnight. At this time the reaction wasdiluted with tetrahydrofuran (20 mL) and treated with approximately 2.0g of polyamine resin (2.63 mmol/g) and approximately 2.5 g ofmethylisocyanate functionalized polystyrene (1.5 mmol/g) and the orbitalshaking was continued at 200 RPM at room temperature for 3 hours. Thereaction vessel was then opened and the solution phase product wasseparated from the insoluble quenched byproducts by filtration andcollection into a vial. After partially evaporation the insolublebyproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate wasevaporated by blowing N2 over the vial and the resulting solid wastriturated with diethyl ether to give an off-white solid. (0.14 g, 41%)

¹H NMR (400 MHz, CD₃OD) δ 7.63 (m, 1H), 7.51 (dd, J=2.2 and 7.2 Hz, 1H),7.45 (t, J=8.4 Hz, 1H) 7.03 (m, 2H), 6.65 (s, 1H), 5.34 (s, 2H), 3.74(s, 2H), 3.51 (s, 2H), 2.80 (s, 4H), 2.08 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −111.31 (1F), −115.72 (1F), −121.41 (1F) ppm. ES-HRMS m/z550.0946 (M+H calcd for C₂₅H₂₄ClF₃N₃O₃ requires 550.0948).

Example 601-603

By following the method of Example 600 and replacing N-methylamine withthe appropriate amine, the compounds of Examples 601-603 are prepared.

Compound % M + H ESHRMS No. R₁ R₂ Yield MF Requires m/z Ex. 601 CH₂CH₂O—CH₂CH₂— 98 C₂₄H₂₁BrF₃N₂O₄ 537.0631 537.0620 Ex. 602 CH₃ CH₂CH₂OH 43C₂₃H₂₁BrF₃N₂O₄ 525.0631 525.0618 Ex. 603 H CH₂C(CH₃)₂OH 65C₂₄H₂₃BrF₃N₂O₄ 539.0783 539.0788

Example 604

methyl4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluorobenzoateStep 1 Preparation of 4 amino-3-fluorobenzoic acid

3-Fluoro-4-aminobenzoic acid was prepared as described in theliterature. (Schmelkes, F. C.; Rubin, M. J. Am. Chem. Soc. 1944, 66,1631-2.)

Step 2 Preparation of methyl 4-amino-3-fluorobenzoate

A 250 mL 3-necked round bottomed flask equipped with a nitrogen inlet,stirbar, addition funnel and thermocouple was charged with4-amino-3-fluorobenzoic acid (11.8 g, 76 mol) and methanol (100 mL). Thesystem was cooled to 0 C and acetyl chloride (7.6 mL, 107 mol) was addeddropwise. The system was warmed to room temperature, the addition funnelwas replaced with a reflux condenser, and was heated to reflux for 6 h.The reaction mixture was cooled to room temperature, quenched withsaturated aqueous NaHCO₃, and extracted with ethyl acetate. The organicextract was washed with brine and concentrated in vacuo to give methylmethyl 4-amino-3-fluorobenzoate as an tan solid (8.2 g, 64%). ¹H NMR(400 MHz, CD₃OD) δ 7.56 (dd, J=1.6 and 8.0 Hz, 1H), 7.52 (dd, J=1.9 and12 Hz, 1H), 6.76 (t, J=8.4 Hz, 1H), 3.81 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −139.05 (1F) ppm. ES-HRMS m/z 170.0565 (M+H calcd for C₈H₉FNO₂requires 170.0612).

Step 3 Preparation of methyl3-fluoro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate

A 250 mL round bottomed flask equipped with stirbar, Dean-Stark trap andreflux condenser was charged with the product of Step 2 (8 g, 47.3mmol), 4-hydroxy-6-methyl-2-pyrone (12 g, 84.6 mmol), andN-methyl-2-pyrrolidine (8 mL). The system was immersed in a 150 C oilbath for 2 hours and was then cooled to room temperature. The reactionmixture was washed with aqueous K₂CO₃ (8.5 g, 200 mL water). The aqueouslayer was washed with ethyl acetate and then was acidified to pH 4-5with glacial HOAc. This was extracted with ethyl acetate, which was thenconcentrated in vacuo. The viscous oil was triturated with acetonitrileand filtered to the title compound as a tan solid (2.3 g, 17%). ¹H NMR(400 MHz, CD₃OD) δ 7.98 (dd, J=1.8 and 8.0 Hz, 1H), 7.91 (dd, J=1.7 and10 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 6.09 (dd, J=0.9 and 2.4 Hz, 1H), 5.77(d, J=2.7 Hz, 1H), 3.94 (s, 3H), 1.97 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −123.00 (1F) ppm. ES-HRMS m/z 278.0781 (M+H calcd forC₁₄H₁₃FNO₄ requires 278.0823).

Step 4 Preparation of methyl4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluorobenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 4 (2.3 g, 8.3 mmol) andN,N-dimethyl formamide (20 mL). 1,8-diazabicyclo[5.4.0]undec-7 ene (1.4mL, 9.1 mmol) was added followed by 2,4-difluorobenzyl bromide (1.2 mL,9.1 mmol). The reaction mixture was stirred at 60 C for 3 h, was pouredinto saturated aqueous NaHCO₃ and was extracted with ethyl acetate. Theorganic layer was washed with brine and concentrated in vacuo. The solidwas triturated with acetonitrile and filtered to give the title compound(2.15 g, 64%). ¹H NMR (400 MHz, CD₃OD) δ 7.99 (dd, J=1.7 and 8.4 Hz,1H), 7.93 (dd, J=1.8 and 10.4 Hz, 1H), 7.55 (m, 1H), 7.48 (t, J=6.8 Hz,1H), 7.02 (m, 2H), 6.18 (dd, J=1.3 and 2.76 Hz, 1H), 6.02 (d, J=2.7 Hz,1H), 5.14 (s, 2H), 3.94 (s, 3H), 1.98 (s, 3H) ppm. ¹⁹F NMR (400 MHz,CD₃OD) δ −111.34 (1F), 115.97 (1F), −122.98 (1F) ppm. ES-HRMS m/z404.1133 (M+H calcd for C₂₁H₁₇F₃NO₄ requires 404.1104).

Step 5 Preparation of methyl4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl2-oxopyridin-1(2H)-yl]-3-fluorobenzoate

A 100 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the product of Step 4 (2.15 g, 5.3 mmol) andN-methyl-2-pyrrolidine (15 mL). After cooling to 0 C, a solution ofN-bromo succinimide (1.03 g, 5.8 mmol) in 10 mL ofN-methyl-2-pyrrolidine was added over 15 minutes. After 15 additionalminutes, the reaction mixture was warmed to room temperature and wasstirred for 1 hour. The mixture was then poured into saturated aqueousNaHCO₃ and extracted with ethyl acetate. The organic layer was washedwith brine and concentrated in vacuo. The residue was triturated withacetonitrile and filtered to give the title compound as a white powder(1.5 g, 59%). ¹H NMR (400 MHz, CD₃OD) δ 8.00 (dd, J=2.0 and 8.4 Hz, 1H),7.95 (dd, J=1.7 and 10 Hz, 1H), 7.64 (q, J=8.8 and 14.4 Hz, 1H), 7.51(t, J=7.6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H),3.95 (s, 3H), 2.01 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.50 (1F),−115.97 (1F), −123.01 (1F) ppm. ES-HRMS m/z 484.0169 (M+H calcd forC₂₁H₁₆BrF₃NO₄ requires 484.0192).

Example 605

4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid

Preparation of4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid.Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoate(30.4 g, 70.1 mmol) was suspended in methanol (150 mL) and dioxane (150mL). 2.5N NaOH (30.8 mL, 77.08 mmol) was added. The resulting mixturewas heated to 50° C. for 8.0 hours. The reaction was partiallyconcentrated and the heterogenous mixture was acidified (pH 2) with 1NHcl. The precipitate was collected by filtration washing with H₂O anddiethyl ether to afford a white solid (29.2 g, 99%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.88 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31 (dt,J=2.4, 9.9 Hz, 1H), 7.18 (app d, J=8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.60(s, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 420.0821(M+H calcd for C₂₁H₁₇ClF₂NO₄ requires 420.0809).

Example 606

4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide

Preparation of4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzamide.4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid (12.0 g, 28.58 mmol) was suspended in tetrahydrofuran (100 mL).2-Chloro-4,6-dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was addedfollowed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The resultingmixture was stirred at room temperature for 1.5 hours at which timeNH₄OH (50.0 mL) was added. The resulting mixture was stirred at roomtemperature for 1 hour and then partially concentrated. The precipitatewas collected by filtration washing with H₂O and diethyl ether toprovide an off-white solid (12.11 g, >100%). ¹H NMR (400 MHz, DMSO-d₆) δ7.91 (br s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H),7.31 (dt, J=2.6, 10.5 Hz, 1H), 7.17-7.12 (m, 1H), 7.13 (app d, J=8.3 Hz,2H), 6.59 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z419.0968 (M+H calcd for C₂₁H₁₈ClF₂N₂O₃ requires 419.0969).

Example 607

4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylbenzamide

Preparation of4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}}-N,N-dimethylbenzamide.4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (20 mL).1-Hydroxybenzotriazole (0.773 g, 5.72 mmol) was added followed by4-methylmorpholine (1.57 mL, 14.28 mmol), dimethylamine (7.14 mL, 2.0 Min tetrahydrofuran, 14.28 mmol) and then1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g,6.66 mmol). The resulting mixture was stirred at room temperature for 3hours at which time the reaction was diluted with H₂O (75 mL). Thereaction mixture was then extracted with ethyl acetate. The combinedorganic extracts were washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. The resulting solid was washed withethyl acetate to provide the title compound as a white solid (1.67 g,78%). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (app q, J=7.8 Hz, H), 7.33 (d,J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.95-6.90 (m, 1H), 6.84 (app dt,J=2.5, 9.4 Hz, 1H), 6.02 (s, 1H), 5.35 (s, 2H), 5.19 (s, 2H), 2.97-2.93(br m, 6H), 2.26 (s, 3H). ES-HRMS m/z 447.1246 (M+H calcd forC₂₃H₂₂ClF₂N₂O₃ requires 447.1282).

Example 608

4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide

Preparation of4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide.4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (10 mL).1-Hydroxybenzotriazole (0.772 g, 5.71 mmol) was added followed by4-methylmorpholine (1.57 mL, 14.28 mmol), 1-amino-2-methyl-2-propanolhydrochloride (1.49 g, 11.90 mmol) and then1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g,6.66 mmol). The resulting mixture was stirred at room temperature for 2days at which time the reaction was diluted with H₂O (50 mL). Thereaction mixture was then extracted with ethyl acetate. The combinedorganic extracts were washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. The resulting solid was washed withdiethyl ether to provide the title compound as a tan solid (2.08 g,89%). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.2 Hz, 2H), 7.51 (app q,J=7.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.93 (app dt,J=1.6, 8.3, 9.4 Hz, 1H), 6.87-6.82 (m, 1H), 6.01 (s, 1H), 5.32 (s, 2H),5.19 (s, 2H), 3.42 (d, J=5.9 Hz, 2H), 2.26 (s, 3H), 1.23 (s, 6H).ES-HRMS m/z 491.1522 (M+H calcd for C₂₅H₂₆ClF₂N₂O₄ requires 491.1544).

Example 609

N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-2-hydroxyacetamideStep 1. Preparation of1-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Example 244 (0.250 g, 0.556 mmol) was suspended in tetrahydrofuran (2.0mL) and cooled in an ice-bath. Borane dimethyl sulfide (0.500 mL, 2.0 Min tetrahydrofuran, 1.00 mmol) was added. The resulting mixture washeated to reflux overnight and then cooled in an ice-bath. The reactionwas quenched by the addition of 6.0 N HCl (5.0 mL) then washed withethyl acetate. The aqueous layer was made alkaline with 2.5 N NaOH andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to provide anoff-white solid (0.180 g, 74%). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (app q,J=7.8 Hz, 1H), 7.44 (app d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 6.95(app dt, J=1.5, 8.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s,2H), 3.93 (s, 2H), 1.96 (s, 3H).

Step 2. Preparation of2-({4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}amino)-2-oxoethyl

Acetoxyacetic acid (0.037 g, 0.310 mmol) was dissolved indichloromethane (2.0 mL). 1-hydroxybenzotriazole (0.021 g, 0.155 mmol)was added followed by 3-(1-cyclohexylcarbodiimide)propyl-functionalizedsilica gel (1.00 g, 0.620 mmol, loading=0.64 mmol/g). After stirring atroom temperature for 15 minutes,1-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(Step 1) (0.180 g, 0.310 mmol) in dichloromethane (2.0 mL) was added.The resulting mixture was stirred at room temperature overnight, atwhich time the reaction mixture was filtered and concentrated.Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol)provided a white solid (0.130 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ 7.58(app q, J=7.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.05 (app d, J=8.3 Hz,2H), 6.97-6.92 (m, 1H), 6.88-6.83 (m, 1H), 6.08 (s, 1H), 5.24 (s, 2H),4.58 (s, 2H), 4.44 (d, J=6.0 Hz, 2H), 2.13 (s, 3H), 1.95 (s, 3H).

Step 3. Preparation ofN-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}-2-hydroxyacetamide.2-({4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzyl}amino)-2-oxoethyl(Step 2) (0.130 g, 0.243 mmol) was dissolved in methanol (5 mL) and H₂O(1 mL). K₂CO₃ (0.055 g, 0.398 mmol) was added and the resulting mixturewas stirred at room temperature for 2 hours. The mixture was thenconcentrated and the residue was partitioned between H₂O and ethylacetate. The organic layer was removed and the aqueous layer was furtherextracted with ethyl acetate. The combined organic layer were washedwith brine, dried over Na₂SO₄, filtered and concentrated to provide anoff-white solid (0.100 g, 84%). ¹H NMR (400 MHz, CDCl₃) δ 7.56 (app q,J=7.7 Hz, 1H), 7.43 (t, J=5.8 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.04 (appd, J=8.3 Hz, 2H), 6.98-6.93 (m, 1H), 6.88-6.83 (m, 1H), 6.11 (s, 1H),5.24 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 3.87 (s, 2H), 1.96 (s, 3H).ES-HRMS m/z 493.0575 (M+H calcd for C₂₂H₂₀BrF₂N₂O₄ requires 493.0569).

Example 610

3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzamide

Example 291-(2.00 g, 4.93 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (1.04 g, 5.91 mmol) were suspendedin tetrahydrofuran (20 mL). 4-Methylmorpholine (1.6 mL, 14.79 mmol) wasadded. The resulting mixture was stirred for 1.5 hours at roomtemperature. NH₄OH (10 mL, 148.00 mmol) was added and the reaction wasstirred for 0.5 hours at room temperature. H₂O (50 mL) andtetrahydrofuran (50 mL) were added and the organic layer was separated.The aqueous phase was extracted with ethyl acetate (75 mL) and thecombined organics were washed with saturated Na₂CO₃ (50 mL), 1N HCl (50mL), and brine (50 mL). The organic phase was dried over Na₂SO₄ andevaporated. The resulting solid was washed with diethyl ether to give awhite solid (1.96 g, 98%). ¹H NMR (400 MHz, DMF-d₆) δ 8.24 (br s, 1H),8.10 (dt, J=1.21, 7.79 Hz, 1H), 7.90 (t, J=1.88 Hz, 1H), 7.79 (app dt,J=6.58, 8.59 Hz, 1H), 7.66 (t, J=7.79 Hz, 1H), 7.57-7.55 (m, 1H), 7.46(br s, 1H), 7.33 (ddd, J=2.55, 9.26, 11.82 Hz, 1H) 7.24-7.19 (m, 1H),6.78 (s, 1H), 5.44 (s, 2H), 2.04 (s, 3H). ES-HRMS m/z 405.0835 (M+Hcalcd for C₂₀H₁₆BrF₂N₂O₃ requires 405.0812).

Example 611

1-(4-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1: Preparation of1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenylcarbamate

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid (8.00 g, 17.23 mmol) was suspended in 1:1 acetonitrile:t-butanol(172 mL). Diphenylphosphoryl azide (5.69 g, 20.68 mmol) andtriethylamine (2.08 g, 20.68 mmol) were added. The reaction was heatedto reflux for 1.5 hours. The reaction mixture was cooled to roomtemperature, concentrated and subjected to chromatography (on silica,ethyl acetate with 10% methanol/hexanes) to afford an off-white solid(6.14 g, 66%).

Step 2:1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenylcarbamate(Step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl in dioxane (5.74mL, 22.94 mmol). The reaction mixture was stirred at room temperaturefor 1 hour then diluted with diethyl ether. The precipitate wascollected by filtration and washed with diethyl ether (3×30 mL) toafford a tan solid (3.45 g, 69%). ¹H NMR (400 MHz, DMF-d₆) δ 7.64 (appdt, J=6.58, 8.59 Hz, 1H), 7.31 (ddd, J=2.55, 9.53, 10.61 Hz, 1H)7.29-7.12 (m, 5H), 6.56 (s, 1H), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s,3H). ES-HRMS m/z 435.0516 (M+H calcd for C₂₀H₁₈BrF₂N₂O₂ requires435.0514).

Example 612

1-(3-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

By following the method for Example 611 and substituting3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoicacid for 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl 2oxopyridin-1(2H)-yl]methyl}benzoic acid, the title compound was prepared(2.65 g, 67%). ¹H NMR (400 MHz, DMF-d₆) δ 7.64 (app dt, J=6.58, 8.59 Hz,1H), 7.39 (t, J=7.79 Hz, 1H), 7.32 (ddd, J=2.55, 9.53, 10.61 Hz, 1H)7.18-7.08 (m, 3H), 6.96 (s, 1H), 6.58 (s, 1H), 5.30 (s, 2H), 5.27 (s,2H), 2.29 (s, 3H). ES-HRMS m/z 435.0513 (M+H calcd for C₂₀H₁₈BrF₂N₂O₂requires 435.0514).

Example 613

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenyl)acetamide

To a reaction vessel (borosilicate culture tube) was added Example611-(0.300 g, 0.689 mmol) and dichloromethane (3.0 mL). A stock solutionof N-methylmorpholine (0.30 M, 3.0 mL) was added and the parallelreaction apparatus was then orbitally shaken (Labline Benchtop OrbitalShaker) at approximately 200 RPM at room temperature for 10 minutes.Acetyl chloride (0.074 mL, 1.033 mmol) was then added to the reactionvessel and the reaction apparatus was orbitally shaken at roomtemperature for 1.5 hours. At this time the reaction was diluted withdichloromethane (15 mL) and treated with approximately 2.1 g ofpolyamine resin (2.63 mmol/g) and approximately 3.8 g ofmethylisocyanate functionalized polystyrene (1.10 mmol/g) and theorbital shaking was continued at 200 RPM at room temperature overnight.The reaction vessel was then opened and the solution phase products wereseparated from the insoluble quenched byproducts by filtration andcollection into a vial. After partial evaporation the insolublebyproducts were rinsed with dichloromethane (2×10 mL). The filtrate wasevaporated by blowing N₂ over the vial to afford a white solid (0.135 g,41%). ¹H NMR (400 MHz, DMF-d₆) δ 7.75 (app dt, J=6.58, 8.59 Hz, 1H),7.63 (d, J=8.59 Hz, 1H), 7-30 (ddd, J=2.55, 9.53, 10.61 Hz, 1H),7.22-7.14 (m, 3H), 6.60 (s, 1H), 5.37 (s, 4H), 2.40 (s, 3H), 2.06 (s,3H). ES-HRMS m/z 477.0600 (M+H calcd for C₂₂H₂₁BrF₂N₂O₃ requires477.0620).

Preparation of Examples 614-616

By following the method for Example 613 and replacing acetyl chloridewith the appropriate acid chloride or sulfamoyl chloride, the compoundsof Examples 614-616 are prepared. The deprotection of the protectedintermediate was accomplished with 1M K₂CO₃ in methanol to afford thetitle compound.

Compound % M + H ES-HRMS No. R Yield MF Requires m/z Ex. 614 CH₂OH 65C₂₂H₂₀BrF₂N₂O₄ 493.0569 493.0593 Ex. 615 CH₂OCOCH₃ 43 C₂₄H₂₂BrF₂N₂O₅535.0675 535.0702 Ex. 616 SO₂N(CH₃)₂ 43 C₂₂H₂₃BrF₂N₃O₄S 542.0555542.0572

Example 617

N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenyl)acetamide

To a reaction vessel (borosilicate culture tube) was added Example 612(0.300 g, 0.689 mmol) and dichloromethane (3.0 mL). A stock solution ofN-methylmorpholine (0.30 M, 3.0 mL) was added and the parallel reactionapparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) atapproximately 200 RPM at room temperature for 10 minutes. Acetylchloride (0.074 mL, 1.033 mmol) was then added to the reaction vesseland the reaction apparatus was orbitally shaken at room temperature for1.5 hours. At this time the reaction was diluted with dichloromethane(15 mL) and treated with approximately 2.1 g of polyamine resin (2.63mmol/g) and approximately 3.8 g of methylisocyanate functionalizedpolystyrene (1.10 mmol/g) and the orbital shaking was continued at 200RPM at room temperature overnight. The reaction vessel was then openedand the solution phase products were separated from the insolublequenched byproducts by filtration and collection into a vial. Afterpartial evaporation the insoluble byproducts were rinsed withdichloromethane (2×10 mL). The filtrate was evaporated by blowing N₂over the vial to afford a white solid (0.167 g, 51%). ¹H NMR (400 MHz,DMF-d₆) δ 7.77 (app dt, J=6.58, 8.59 Hz, 1H), 7.69 (d, J=8.32 Hz, 1H),7.41 (br s, 1H), 7.34-7.17 (m, 3H), 6.88 (d, J=7.65 Hz, 1H), 6.63 (s,1H), 5.39 (s, 3H), 5.38 (s, 2H), 2.40 (s, 3H), 2.06 (s, 3H). ES-HRMS m/z477.0620 (M+H calcd for C₂₂H₂₁BrF₂N₂O₃ requires 477.0620).

Preparation of Example 618-620

By following the method for Example 617 and replacing acetyl chloridewith the appropriate acid chloride or sulfamoyl chloride, the compoundsof Examples 618-620 are prepared. The deprotection of the protectedintermediate was accomplished with 1M K₂CO₃ in methanol to afford thetitle compound.

Compound % M + H ES-HRMS No. R. Yield MF Requires m/z Ex. 618 CH₂OH 72C₂₂H₂₀BrF₂N₂O₄ 493.0569 493.0604 Ex. 619 CH₂OCOCH₃ 53 C₂₄H₂₂BrF₂N₂O₅535.0675 535.0692 Ex. 620 SO₂N(CH₃)₂ 21 C₂₂H₂₃BrF₂N₃O₄S 542.0555542.0567

Example 621

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N′-methylurea

Preparation of(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N′-methylurea.EXAMPLE 159 (150 mg, 0.33 mmol) was dissolved in N,N-dimethylacetamide(5 mL) and cooled to 0° C. 4-Nitrophenyl chloroformate (100 mg, 0.5mmol) was added, followed by N,N-diisopropylethylamine (0 15 mL, 0.85mmol) and the reaction was stirred at 0° C. for 5 minutes. N-Methylamine(0.5 mL, 1.0 mmol, 2M in tetrahydrofuran) was added and the reaction wasallowed to reach ambient temperature and stirred for 1 hour. Thereaction was then diluted with tetrahydrofuran (40 mL) and polyamineresin (1.3 g, 2.81 mmol/g) and methylisocyanate functionalizedpolystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 16hours at ambient temperature, filtered, and the resulting filtrateconcentrated to an oil that was triturated with ether. The resultingwhite solid was collected, washed with ether, and dried (87 mg, 52%). ¹HNMR (400 MHz, CD₃OD) δ 7.61 (app q, J=8.4 Hz, 1H); 7.24 (d, J=8.0 Hz,2H), 7.07 (d, J=8.0 Hz, 2H), 7.02 (app t, J=8.4 Hz, 2H), 6.47 (s, 1H),5.39 (s, 2H), 5.28 (s, 2H), 4.26 (s, 2H); 2.68 (s, 3H); 2.34 (s, 3H).ES-HRMS m/z 506.0862 (M+H calcd for C₂₃H₂₃BrF₂N₃O₃ requires 506.0885).

Example 622

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N′-(2-hydroxy-2-methylpropyl)urea

Preparation ofN-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N′-(2-hydroxy-2-methylpropyl)urea.EXAMPLE 159 (300 mg, 0.67 mmol) was dissolved in N,N-dimethylacetamide(5 mL) and cooled to 0° C. 4-Nitrophenyl chloroformate (200 mg, 1.0mmol) was added, followed by N,N-diisopropylethylamine (0.3 mL, 1.7mmol) and the reaction was stirred at 0° C. for 5 minutes.3-Amino-2-methyl 2-propanol (248 mg, 2.0 mmol) was added and thereaction was allowed to reach ambient temperature and stirred for 3 h.The reaction was then diluted with tetrahydrofuran (40 mL) and polyamineresin (1.3 g, 2.81 mmol/g) and methylisocyanate functionalizedpolystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 16hours at ambient temperature, filtered, and the resulting filtrateconcentrated to an oil that was triturated with ether. The resultingwhite solid was purified by chromatography (silica gel, hexane/ethylacetate/methanol) followed by reversed phase chromatography (C₁₈, 0.1%aqueous trifluoroacetic acid/acetonitrile) to yield an off-white solid(43 mg, 11%). ¹H NMR (400 MHz, CDCl₃) δ 7.56 (app q, J=8.0 Hz, 1H); 7.12(d, J=8.4 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 7.02 (app dt, J=1.6, 8.0 Hz,2H), 6.83-6.88 (m, 1H), 6.06 (s, 1H), 5.26 (s, 2H), 5.21 (s, 2H); 4.22(s, 2H); 3.09 (s, 2H); 2.30 (s, 3H); 1.14 (s, 6H). ES-HRMS m/z 564.1279(M+H calcd for C₂₆H₂₉BrF₂N₃O₄ requires 564.1304).

Example 623

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)piperidine-1-carboxamide

By following the general method for Example 622 and substitutingpiperidine (170 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the titlecompound was prepared and purified by chromatography (silica gel,hexane/ethyl acetate/methanol) yielding an oil that was triturated withether to afford a white solid (107 mg, 28%). ¹H NMR (400 MHz, CDCl₃) δ7.56 (app q, J=8.0 Hz, 1H); 7.23 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz,2H), 7.02 (app t, J=8.0 Hz, 2H), 6.81-6.88 (m, 1H), 5.97 (s, 1H), 5.32(s, 2H), 5.19 (s, 2H); 4.37 (s, 2H); 3.34-3.28 (m, 4H); 2.29 (s, 3H);1.68-1.50 (m, 6H). ES-HRMS m/z 560.1365 (M+H calcd for C₂₇H₂₉BrF₂N₃O₃requires 560.1355).

Example 624

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)morpholine-4-carboxamide

By following the general method for Example 622 and substitutingmorpholine (175 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the titlecompound was prepared and purified by chromatography (silica gel,hexane/ethyl acetate/methanol) followed by reversed phase chromatography(C₁₈, 0.1% aqueous trifluoroacetic acid/acetonitrile) to yield anoff-white solid (51 mg, 13%). ¹H NMR (400 MHz, CDCl₃) δ 7.55 (app q,J=8.0 Hz, 1H); 7.17 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.94 (appdt, J=2.4, 8.0 Hz, 2H), 6.82-6.87 (m, 1H), 6.02 (s, 1H), 5.27 (s, 2H),5.19 (s, 2H); 4.33 (s, 2H); 3.65-3.62 (m, 4H); 3.34-3.36 (m, 4H); 2.28(s, 3H). ES-HRMS m/z 562.1152 (M+H calcd for C₂₆H₂₇BrF₂N₃O₄ requires562.1148).

Example 625

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)piperazine-1-carboxamidehydrochloride

By following the general method for Example 622 and substituting1-Boc-piperazine (372 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol thetitle compound was prepared from its N-t-butoxycarbonyl protectedintermediate that was purified by chromatography (silica gel,hexane/ethyl acetate/methanol). Deprotection was accomplished with 4NHCl in dioxane to afford the title compound as its hydrochloride salt(78 mg, 19%). ¹H NMR (400 MHz, CD₃OD) δ 7.61 (app q, J=7.6 Hz, 1H); 7.26(d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.08-7.00 (m, 2H), 6.48 (s,1H), 5.41 (s, 2H), 5.28 (s, 2H); 4.31 (s, 2H); 3.65-3.62 (m, 4H);3.21-3.17 (m, 4H); 2.35 (s, 3H) ES-HRMS m/z 561.1318 (M+H calcd forC₂₆H₂₈BrF₂N₄O₃ requires 561.1307).

Example 626

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N′-(2-hydroxyethyl)urea

By following the general method for Example 622 and substitutingethanolamine (121 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol thetitle compound was prepared and purified by chromatography (silica gel,hexane/ethyl acetate/methanol) to yield an off-white solid (130 mg,36%). ¹H NMR (400 MHz, CDCl₃) δ 7.54 (app q, J=7.6 Hz, 1H); 7.13 (d,J=8.4 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 6.96-6.92 (m, 1H); 6.83-6.88 (m,1H), 6.09 (s, 1H), 5.26 (s, 2H), 5.21 (s, 2H); 4.24 (s, 2H); 3.56 (t,J=4.8 Hz, 2H); 3.21 (t, J=4.8 Hz, 2H); 2.31 (s, 3H). ES-HRMS m/z536.0948 (M+H calcd for C₂₄H₂₅BrF₂N₃O₄ requires 536.0991).

Example 627

N′-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-N,N-dimethylurea

By following the general method for Example 622 and substitutingN,N-dimethylamine (1.0 mL, 2.0 mmol, 2M in tetrahydrofuran) for3-amino-2-methyl-2-propanol the title compound was prepared and purifiedby chromatography (silica gel, hexane/ethyl acetate/methanol) yieldingan oil that was triturated with ether to afford a white solid (65 mg,19%). ¹H NMR (400 MHz, CDCl₃) δ 7.56 (app q, J=8.0 Hz, 1H); 7.22 (d,J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.93 (app dt, J=2.0, 8.0 Hz, 1H);6.87-6.81 (m, 1H); 5.97 (s, 1H), 5.31 (s, 2H), 5.19 (s, 2H); 4.36 (s,2H); 2.89 (s, 6H); 2.28 (s, 3H). ES-HRMS m/z 520.1072 (M+H calcd forC₂₄H₂₅BrF₂N₃O₃ requires 520.1042).

Example 628

N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-4-hydroxypiperidine-1-carboxamide

By following the general method for Example 622 and substituting4-Hydroxypiperidine (202 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanolthe title compound was prepared and purified by chromatography (silicagel, hexane/ethyl acetate/methanol) yielding an oil that was trituratedwith ether to afford a white solid (41 mg, 11%). ¹H NMR (400 MHz, CDCl₃)δ 7.56 (app q, J=8.0 Hz, 1H); 7.20 (d, J=7.6 Hz, 2H), 7.06 (d, J=8.0 Hz,2H), 6.94 (app t, J=8.0 Hz, 1H); 6.84 (app t, J=8.0 Hz, 1H); 5.99 (s,1H), 5.29 (s, 2H), 5.19 (s, 2H); 4.34 (s, 2H); 3.84-3.70 (m, 3H);3.04-2.92 (m, 3H); 2 28 (s, 3H); 1.84-1.81 (m, 2H); 1.47-1.44 (m, 2H).ES-HRMS m/z 576.1348 (M+H calcd for C₂₇H₂₉BrF₂N₃O₄ requires 576.1304).

Example 629

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylbenzenesulfonamideStep 1: Preparation of 4-Bromomethyl-N,N-dimethylbenzenesulfonamide

4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolvedin tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M intetrahydrofuran) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) wereadded, and the reaction was allowed to stir at ambient temperature for 2hours. The reaction was concentrated to an oil that was partitionedbetween water and ethyl acetate and extracted with ethyl acetate. Theorganic extracts were combined, washed with brine, dried over Na₂SO₄,and filtered. The resulting filtrate was concentrated to an oil whichdeposited needles that were a mixture of the title compound and4-chloromethyl N,N-dimethylbenzenesulfonamide The resulting needles werecollected and dried (2.3 g, 44%). ES-MS m/z 534 (M+H) and 578 (M+H).

Step 2: Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylbenzenesulfonamide.3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(1H)-one (300 mg, 0.91mmol) was suspended in 1,4-dioxane (50 mL).4-(Bromomethyl)-N,N-dimethylbenzenesulfonamide (from step 1) (300 mg,1.09 mmol) was added followed by sodium hydride (45 mg, 1.09 mmol, 60%in mineral oil). The reaction was heated to 80° C. and stirred for 16hours after which more sodium hydride (45 mg, 1.09 mmol, 60% in mineraloil) and sodium iodide (150 mg, 1.0 mmol) were added. The reaction wasallowed to stir at 80° C. for 4 hours more. The reaction was thenfiltered through Celite® and the filtrate was concentrated to an oilthat was purified by chromatography (silica gel, hexane/ethyl acetate)followed by reversed phase chromatography (C₁₈, 0.1% aqueoustrifluoroacetic acid/acetonitrile) to yield an off-white solid (41 mg,8%). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.4 Hz, 2H); 7.57 (app q, J=76Hz, 1H); 7.29 (d, J=8.0 Hz, 2H); 6.95 (app dt, J=2.0, 8.0 Hz, 1H),6.88-6.83 (m, 1H); 6.05 (s, 1H), 5.42 (s, 2H), 5.22 (s, 2H); 2.69 (s,6H); 2.29 (s, 3H). ES-HRMS m/z 527.0439 (M+H calcd for C₂₂H₂₂Br₂F₂N₂O₄Srequires 527.0446).

Example 630

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamideStep 1: Preparation of4-Bromomethyl-N-(2-hydroxyethyl)benzenesulfonamide

4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolvedin tetrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) andN,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and thereaction was allowed to stir at ambient temperature for 30 minutes. Thereaction was concentrated to an oil that was partitioned between waterand ethyl acetate and extracted with ethyl acetate. The organic extractswere combined, washed with brine, dried over Na₂SO₄, and filtered. Theresulting filtrate was concentrated to an oil that was a mixture of thetitle compound and 4-chloromethyl N-(2-hydroxyethyl)benzenesulfonamide.The resulting oil was dried in vacuo (3.7 g, 68%). ES-MS m/z 250 (M+H)and 294 (M+H).

Step 2: Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)benzenesulfonamide

The title compound was prepared essentially according to the proceduredescribed in Step 2 of Example 629, using4-Bromomethyl-N-(2-hydroxyethyl)benzenesulfonamide (from step 1). ¹H NMR(400 MHz, CDCl₃) δ 7.81 (d, J=8.4 Hz, 2H); 7.61 (app q, J=7.6 Hz, 1H);7.30 (d, J=8.4 Hz, 2H); 6.95 (app t, J=8.4 Hz, 2H), 6.53 (s, 1H), 5.49(s, 2H), 5.30 (s, 2H); 3.50 (t, J=6.0 Hz, 2H); 2.92 (t, J=6.0 Hz, 2H);2.36 (s, 3H). ES-HRMS m/z 543.0453 (M+H calcd for C₂₂H₂₂Br₂F₂N₂O₅Srequires 543.0395).

Example 631

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzenesulfonamideStep 1: Preparation of4-Bromomethyl-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

4-(Bromomethyl)benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolvedin tetrahydrofuran. 3-Amino-2-methyl-2-propanol (1.0 g, 8 mmol) andN,N-diisopropylethylamine (1.5 mL, 8.8 mmol) were added, and thereaction was allowed to stir at ambient temperature for 30 minutes. Thereaction was concentrated to an oil that was partitioned between waterand ethyl acetate and extracted with ethyl acetate. The organic extractswere combined, washed with brine, dried over Na₂SO₄, and filtered. Theresulting filtrate was concentrated to an oil that was a mixture of thetitle compound and4-chloromethyl-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide. Theresulting oil was dried in vacuo (1.9 g, 81%).

Step 2: Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

The title compound was prepared essentially according to the proceduredescribed in Step 2 of Example 629, using4-Bromomethyl-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide from step1). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2H); 7.56 (app q, J=7.6Hz, 1H); 7.26 (d, J=8.4 Hz); 6.95 (app t, J=8.4 Hz, 1H), 6.86-6.83 (m,1H); 6.07 (s, 1H), 5.41 (s, 2H), 5.22 (s, 2H); 4.98 (t, J=6.4 Hz, 1H);2.84 (d, J=6.4 Hz, 2H); 2.29 (s, 3H); 1.21 (s, 6H). ES-HRMS m/z 571.0684(M+H calcd for C₂₄H₂₆Br₂F₂N₂O₅S requires 571.0708).

Example 632

3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-pyrazol-3-ylmethyl)-1H-pyridin-2-oneStep 1. Preparation of 4-Hydroxy-6-methyl-1H-pyridin-2-one

4-Hydroxy-6-methyl-pryan-2-one (25.8 g, 0.2 mol) was dissolved in 180 mlof concentrated ammonium hydroxide. The reaction was heated at refluxedfor 4 hours. The reaction was cooled to room temperature and evaporatedon a rotary evaporator to a quarter of the original volume. Theresulting solid was filtered, washed with cold water, hexanes, and driedin a vacuum oven overnight to give a white solid (25 g, 98%): ¹H NMR(300 MHz, DMSO-d₆) δ 10.94 (br s, 1H), 10.34 (s, 1H), 5.59 (d, J=1.4 Hz,1H), 5.32 (d, J=2.0 Hz, 1H), 2.07 (s, 3H).

Step 2. Preparation of 3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one

4-Hydroxy-6-methyl-1H-pyridin-2-one (25 g, 0.2 mol) andN-chlorosuccinimide (29.4 g, 0.22 mol) were dissolved in 200 mL ofacetic acid. The reaction was heated at 115° C. for 6 hours. Thereaction was cooled to room temperature, the solid was filtered, andwashed with acetic acid and hexanes. The solid was dried in a vacuumoven overnight to give a white solid (19.2 g, 60%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.46 (br s, 1H), 11.04 (s, 1H), 5.79 (s, 1H), 2.09 (s, 3H).

Step 3. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1H-pyridin-2-one

3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one (19.2 g, 0.12 mol) and DBU(19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP.2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and thereaction was heated at 80° C. for 6 hours. The reaction was cooled toroom temperature, the solid was filtered, and washed with NMP andhexanes. The solid was dried in a vacuum oven overnight to give a whitesolid (4.4 g, 13%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (br s, 1H), 7.63(app q, J=9 Hz, 1H), 7.33 (app t, J=10 Hz, 1H), 7.16 (app t, J=9 Hz,1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).

Step 4. Preparation of 3-Methylpyrazole-1-carboxylic acid tert-butylester

3-Methyl-1H-pyrazole (5.3 g, 65 mmol), DMAP (0.79 g, 6.5 mmol), anddi-tert-butyl dicarbonate (2.8 g, 13 mmol) were at room temperature in90 mL of CH₃CN for 1 hour. The reaction was evaporated on a rotaryevaporator, and the resulting solid dissolved in EtOAc, washed with 1 NHCl, water and brine, dried (MgSO₄), filtered, and evaporated on arotary evaporator to give a light yellow oil (11.4 g, 96%): ¹H NMR (300MHz, CDCl₃) δ 7.96 (d, J=2.7 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 2.32 (s,3H), 1.63 (s, 9H).

Step 5. Preparation of 3-Bromomethylpyrazole-1-carboxylic acidtert-butyl ester

3-Methylpyrazole-1-carboxylic acid tert-butyl ester (6.0 g, 33 mmol),N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) weredissolved in 20 mL of carbon tetrachloride. The reaction was heated atreflux for 16 h. The reaction was cooled to room temperature, filtered,and concentrated under reduced pressure. Purification by flash columnchromatography (silica, 1:4 EtOAc/hexanes) gave a light yellow oil (4.5g, 53%): ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=2.6 Hz, 1H), 6.47 (d,J=2.6 Hz, 1H), 4.48 (s, 2H), 1.64 (s, 9H).

Step 6. Preparation of3-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester

3-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester was prepared by a procedure similar to the onedescribed for Example 401 gave a yellow solid (1.4 g, 39%): ¹H NMR (300MHz, CDCl₃) δ 7.53-7.49 (m, 2H), 6.97-6.81 (m, 2H), 6.35 (d, J=2.0 Hz,1H), 6.01 (s, 1H), 5.32 (s, 2H), 5.26 (s, 2H), 2.52 (s, 3H), 1.62 (s,9H).

Step 7. Preparation of the title compound Example 6323-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]pyrazole-1-carboxylicacid tert-butyl ester (0.16 g, 0.34 mmol) was heated to 140° C. for 16h. The reaction mixture was cooled to room temperature.Recrystallization from methylene chloride/hexanes provided an off-whitesolid (1.0 g, 91%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.67 (br s, 1H),7.67-7.60 (m, 2H), 7.34 (dt, J=10.5, 2.5 Hz, 1H), 7.17 (dt, J=8.5, 1.6Hz, 1H), 6.52 (s, 1H), 6.10 (d, J=1.9 Hz, 1H), 5.27 (s, 2H), 5.20 (s,2H), 2.48 (s, 2H).

Example 633

3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-oneStep 1. Preparation of5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester

5-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester was prepared by a procedure similar to the onedescribed for Example 632 as an off-white solid (2.5 g, 61%): ¹H NMR(300 MHz, DMSO-d₆) δ 8.00 (d, J=8.5 Hz, 1H), 7.70-7.62 (m, 2H),7.39-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.70 (d, J=3.8 Hz, 1H), 6.66 (s,1H), 5.40 (s, 2H), 5.29 (s, 2H), 2.33 (s, 3H), 1.62 (s, 9H).

Step 2. Preparation of3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one

5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamicacid tert-butyl ester (1.08 g, 2.1 mmol) dissolved in 40 mL of DMSO wasstirred at 120° C. for 20 hours. The reaction was cooled to roomtemperature, diluted with water, and washed 5 times with ethyl acetate.The combined organics were washed 1 time with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. ¹H NMR (300 MHz,DMSO-d₆) δ 11.1 (br s, 1H), 7.67 (d, J=6.7 Hz, 1H), 7.36-7.32 (m, 2H),7.23 (s, 1H), 7.18 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.4, 1.2 Hz, 1H), 6.57(s, 1H), 6.38 (s, 1H), 5.37 (s, 2H), 5.29 (s, 2H), 2.35 (s, 3H).

Step 3.3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one(, from Step 2) (1-7 g, 4.1 mmol) was stirred in 26 mL of acetic acidand NaCNBH₃ (0.27 g, 4.3 mmol) was added portionwise. The reaction wasstirred for 1 hour. The reaction was diluted water, and washed 5 timeswith ethyl acetate. The combined organics were washed 1 time with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica, 100% EtOAc) gave awhite solid (1.2 g, 71%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (app q, J=8.5Hz, 1H), 7.34 (dt, J=9.5, 2.6 Hz, 1H), 7.17 (app t, J=8.5, 1H), 6.82 (s,1H), 6.72 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.48(br s, 1H), 5.27 (s, 2H), 5.13 (s, 2H), 3.37 (t, J=8.3 Hz, 2H), 2.82 (t,J=8.3 Hz, 2H), 2.35 (s, 3H).

Example 634

5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-1,3-dihydro-indol-2-oneStep 1. Preparation of5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-3,3-dibromo-1H-indol-2-one

3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-indol-5-ylmethyl)-1Hpyridin-2-one (0.45 mg, 1.1 mmol) (example 633, step 2) was suspended in11 mL of tert-butanol and pyridinium bromide perbromide (1.04 g, 3.3mmol) was added portionwise. The reaction was stirred for 16 hours. Thereaction was diluted with water, and washed 4 times with ethyl acetate.The combined organics were washed 1 time with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. Trituration withmethylene chloride gave an off-white solid (0.25 g, 39%): ¹H NMR (300MHz, DMSO-d₆) δ 11.26 (br s, 1H), 7.66 (app q, J=8.6 Hz, 1H), 7.48 (s,1H), 7.35 (dt, J=10.5, 2.5 Hz, 1H), 7.18 (dt, J=8.7, 1.9, 1H), 7.05 (dd,j 8.2, 1.5, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 5.29 (s, 4H),2.36 (s, 3H).

Step 2.5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-3,3-dibromo-1H-indol-2-one(0.2 g, 0.34 mmol) was suspended in 5 mL of acetic acid, and zinc metal(0.22 g, 3.4 mmol) was added. The reaction was stirred for 48 hours. Thereaction was diluted with water, and washed 2 times with ethyl acetate.The combined organics were washed 1 time with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. Purification by flashcolumn chromatography (silica, 100% EtOAc) gave a white solid (0.12 g,82%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.37 (br s, 1H), 7.65 (app q, J=6.9Hz, 1H), 7.34 (dt, J=8.2, 2.5 Hz, 1H), 7.18 (dt, J=7.1, 1.9, 1H), 6.98(br s, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 5.28 (s, 2H), 5.23 (s,2H), 3.44 (s, 2H), 2.34 (s, 3H).

Example 635

N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin2-yl)methyl]-N-methylmethanesulfonamide

To a suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one(0.16 g, 0.34 mmol) in acetonitrile at 0° C. was added triethylamine(0.043 g, 0.42 mmol), followed by the addition of methanesulfonylchloride (0.047 g, 0.41 mmol) and stirred at room temperaturefor 1 h under argon atmosphere. The solvents were removed in vacuo andthe residue was triturated with water and filtered. It was washed withwater an, acetonitrile and dried in vacuo to afford 0.11 g of material.¹H NMR (CD₃OD/400 MHz) δ 8.62 (s, 1H), 8.55 (s, 1H), 7.61 (m, 1H), 7.0(m, 2H), 6.53 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 4.49 (s, 2H), 2.95(s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz)-111.70(m) and −116.07 (m); ES-HRMS m/z 543.0515 (M+H calcd for C₂₁H₂₂BrF₂N₄O₄Srequires 543.0508).

Example 636

Methyl(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl(methyl)carbamate

To a cold (5° C.) solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one(0.20 g, 0.4 mmol) in DMF (2.0 ml), was added methylchloroformate (0.049g, 0.52 mmol), followed by the addition of triethylamine (0.072 g, 0.71mmol). The mixture was stirred at 5° C. for 30 min and at roomtemperature for an additional 30 min and concentrated in vacuo. Theresidue was partitioned between water (5.0 mL) and EtOAc (10.0 mL). Theorganic extract was washed with water, dried (Na₂SO₄), and concentratedto dryness. The resulting material was purified by reverse-phase HPLCusing 10-90% CH₃CN/Water gradient (60 min) at a flow rate of 70 mL/min.The appropriate fractions (m/z=523 M+H) were combined and freeze driedto give a white powder. This was partitioned between 5% NaHCO₃ (10 mL)and EtOAc (15 mL). The organic layer was washed with water, dried(Na₂SO₄), and concentrated to dryness to afford the title compound (0.12g, 53%) as a white powder: ¹H NMR (CD₃OD/400 MHz) δ 8.59 (s, 1H), 8.41(m, 1H), 7.60 (m, 1H), 7.05 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2H), 5.29(s, 2H), 4.58 (s, 2H), 3.69 and 3.64 (s, 3H), 2.97 (s, 3H), 2.85 (s,3H), and 2.55 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz)-111.69 (m) and −116.09(m); ES-HRMS m/z 523.0775 (M+H calcd for C₂₂H₂₂BrF₂N₄O₄ requires523.0787).

Example 637

N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-N,2-dimethylpropanamide

To a cold (5° C.) solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one(0.24 g, 0.52 mmol) in DMF (2.0 ml), was added 2-acetoxyisobutyrylchloride (0.093 g, 0.56 mmol), followed by the addition of triethylamine(0.072 g, 0.71 mmol). The mixture was stirred at room temperature for anadditional 2 h and concentrated in vacuo. The residue was partitionedbetween water (5.0 mL) and EtOAc (15.0 mL). The EtOAc extract was washedwith water, dried (Na₂SO₄), and concentrated to dryness. The resultingmaterial (0.2 g) was stirred with 1M. LiOH (0.5 mL, MeOH,/Water 1:1 v/v)at room temperature for 3 h, cooled, acidified with trifluoroacetic acidand the product was purified by reverse-phase HPLC using 10-90%CH₃CN/Water gradient (60 min) at a flow rate of 70 mL/min. Theappropriate fractions (m/z=551 M+H) were combined and freeze dried togive a white powder. This was partitioned between 5% NaHCO₃ (10 mL) andEtoAc (15 mL). The organic layer was washed with water, dried (Na₂SO₄),and concentrated to dryness to afford the title compound (0.075 g) as awhite powder: ¹H NMR (CD₃OD/400 MHz) δ 8.59 (s, 1H), 8.41 (br, 1H), 7.60(m, 2H), 7.01 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2 h), 5.29 (s, 2H),

Example 638

5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N-(2hydroxy-2-methylpropyl)pyrazine-2-carboxamide

To a solution of5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid (0.42 g, 0.9 mmol) in DMF (3.0 mL) was added isobutylchloroformate(0.126 g, 0.13 mmol) followed by the addition of N-methylmorpholine(0.11 g, 1.1 mmol) and stirred at −10° C., under argon atmosphere. After20 min, added a solution of 1,1 dimethyl-2-aminoethanol hydrochloride(0.135 g, 1.1 mmol) in DMF (2.0 mL) containing N-methylmorpholine (0.11g, 1.1 mmol). The mixture was stirred at room temperature for 1 h, andconcentrated to dryness in vacuo. The resulting residue was purified byreverse-phase HPLC using 10-90% CH₃CN/Water gradient (60 min) at a flowrate of 70 mL/min. The appropriate fractions (m/z=537 M+H were combinedand freeze dried to give a white powder. This was partitioned between 5%NaHCO₃ (10 mL) and EtOAc (15 mL). The organic layer was washed withwater, dried (Na₂SO₄), and concentrated to dryness to afford the titlecompound (0.35 g, 75%) as a white powder: ¹H NMR (CD₃OD/400 MHz) δ 9.1(d, 1H, J=1.6 Hz), 8.71 (d, 1H, J=1.6 Hz), 7.61 (m 1H), 7.02 (m, 2H),6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2 h). 3.30 (s, 2 h), 2.55 (s, 3H),and 1.21 (s, 6H); ¹⁹F NMR (CD₃OD/400 MHz) −111.67 (m) and −116.05 (m);ES-HRMS m/z 537.0948 (M+H calcd for C₂₃H₂₄BrF₂N₄O₄ requires 537.0943).

Example 639

1-[(5-Aminopyrazin-2-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onetrifluoroacetate A mixture of5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylicacid (0.70 g, 1.5 mmol) diphenylphosphoryl azide (0.51 g, 1.8 mmol) indimethylacetamide (15.0 mL) and t-butanol (5.0 mL) containingtriethylamine (0.18 g, 1.8 mmol) was heated at 90° C. for 6 h underargon atmosphere. The reaction mixture was cooled, filtered theprecipitate. It was washed with acetonitrile and dried to obtain 0.22 gof the unreacted acid. The combined filtrate and the washings wereconcentrated in vacuo and the resulting material was purified byreverse-phase HPLC using 10 90% CH₃CN/Water gradient (60 min) at a flowrate of 70 mL/min. The appropriate fractions (m/z=437 M+H were combinedand freeze dried to give the title compound (0.21 g, 37%) as a whitepowder: ¹H NMR (DMSO-d₆/400 MHz) δ7.88 (d, 1H, J=1.2 Hz), 7.75 (d, 1H,J=1.2 Hz), 7.61 (m 1H), 7.34 (m, 1H), 7.18 (m, 1H), 6.49 (s, 1H), 5.25(s, 2H), 5.10 (s, 2H), and 2.49 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz) −111.72(m) and −116.11 (m); ES-HRMS m/z 437.0402 (M+H calcd for C₁₈H₁₆BrF₂N₄O₂requires 437.0419).

Example 640

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl)methyl]pyridin-2(1H)-onetrifluoroacetate Step 1: Preparation of (2-methylpyrimidin-5-yl)methanoltrifluoroacetate

To solution of methyl 2-methylpyrimidinecarboxylate (2.6 g, 17.1 mmol)in THF was added dropwise diisobutylaluminumhydride (39.5 mL, 1Msolution in THF) and stirred at −20° C. under argon atmosphere for 1.5h, and at room temperature for 2 h. The reaction was quenched by theaddition of powdered sodiumsulphate decahydrate (25 g), added THF (25mL) and stirred at room temperature for 1 h. This mixture was allowed tostand in the refrigerator overnight and filtered through a celite pad.The precipitate was thoroughly with warm THF (100 mL) containing 10%ethanol. The combined washings and the filtrate were concentrated toafford a yellow syrup, which was purified by reverse-phase HPLC using10-90% CH₃CN/Water gradient (60 min) at a flow rate of 70 mL/min. Theappropriate fractions (m/z=125 M+H) were combined and lyophilized togive the title compound (0.67 g, 32%) as its trifluoroacetate salt: ¹HNMR (CD₃OD/400 MHz) δ8.65 (s, 2H) 4.62 (s, 2H), and 2.66 (s, 3H);ES-HRMS m/z 125.0678 (M+H calcd for C₆H₉N₂O requires 125.0709).

Step 2: Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl)methyl]pyridin-2(1H)-onetrifluoroacetate

To a solution of (2-methylpyrimidin-5-yl)methanol trifluoroacetate (0.9g, 3.76 mmol) in dichloromethane (10 mL) at 0° C., was addedtriethylamine (0.95 g, 9.41 mmol), followed by the addition ofmethanesulfonyl chloride (0.59 g, 5.17 mmol) and stirred at 0° C. for 1h. After stirring for 1 h at room temperature, additional triethylamine(0.22 g) and methanesulfonyl chloride (0.15 g) were added and themixture was stirred at room temperature for another hour under argonatmosphere. The reaction was quenched by the addition of cold water (15mL) and stirred for 15 min. The organic layer was washed with water,followed by 5% sod. bicarbonate (2×15 mL), water, and dried (Na₂SO₄).After the removal of the solvent under reduced pressure, the residue wasdried in a desiccator under vacuum for 4 h. This material was suspendedin THF (10 mL) and DMF (5.0 mL), added3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(1H)-one (0.5 g, 1.52mmol) and NaH (0.04 g). The resulting mixture was heated at 65° C. for16 h under argon atmosphere. The solvents were distilled under vacuumand the residue was purified by reverse-phase HPLC using 10-90%CH₃CN/Water gradient (60 min) at a flow rate of 70 mL/min. Theappropriate fractions (m/z=436 M+H) were combined and freeze dried togive the title compound (0.045 g,) as its trifluoroacetate salt: ¹H NMR(CD₃OD/400 MHz) δ8.58 (s, 2H) 7.61 (m, 1H), 7.01 (m, 2H), 6.53 (s, 1H),5.37 (s, 2 h), 5.29 (s, 2H), 2.65 (s, 3H), and 2.46 (s, 3H); ¹⁹F NMR(CD₃OD/400 MHz) −111.62 (m), and −116.08 (m); ES-HRMS m/z 436 0433(M+Hcalcd for C₁₉H₁₇BrF₂N₃O₂ requires 436.0467).

Example 641

3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-hydroxy-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-one

A mixture of 4-hydroxy-6-methyl-2-pyrone (3.75 g, 0.029 mol) and5-aminoindazole (4.0 g, 0.03 mol) in water (70 ml) was heated at 90° C.under argon for 1 h. The mixture was cooled, decanted the supernatantand residue was triturated with ethanol, cooled and filtered the solid.It was washed with cold ethanol, and dried. ¹H NMR (CD₃OD/400 MHz) δ8.11(s, 1H), 7.64 (m, 2H), 7.18 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2.0 Hz)6.07 (m, 1H), 5.81 (d, 1H, J=2.8 Hz), and 1.94 (s, 3H); ES-HRMS m/z 2420962(M+H calcd for C₁₃H₁₂N₃O₂ requires 242.0924).

Step 2

A mixture of 4-hydroxy-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-one(0.2 g, 0.83 mmol), N-bromosuccinmide (0.15 g, 0.84 mmol) indichloromethane (4.0 mL) and acetic acid (1.0 mL) was stirred at roomtemperature under argon atmosphere for 2.5 h. After the removal of thesolvents, the residue was dried in vacuo for 4 h in a desiccator. It wasthen suspended in DMF (3.0 mL), potassium carbonate (0.19), and 2,4difluorobenzyl bromide were added and mixture was stirred at roomtemperature for 3 h. DMF was distilled in vacuo and the residue waspurified by reverse-phase HPLC using 10-90% CH₃CN/Water gradient (60min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=537M+H) were combined and freeze dried to give a white powder. This waspartitioned between 5% NaHCO₃ (10 mL) and EtOAc (15 mL). The organiclayer was washed with water, dried (Na₂SO₄), and concentrated to drynessto afford the title compound (0.075 g) as a white powder: ¹H NMR(CD₃OD/400 MHz) δ8.13 (s, 1H), 7.68 (m, 3H), 7.20 (2d, 1H, J=1.2 Hz),7.05 (m, 2H), 6.61 (s, 1H), 5.35 (s, 2H), and 2.05 (s, 3H); ¹⁹F NMR(CD₃OD/400 MHz)-111.62 (m) and −116.02 (m); ES-HRMS m/z 446.0305 (M+Hcalcd for C₂₀H₁₅BrF₂N₃O₂ requires 446.0310).

Example 642

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-6-yl)-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-hydroxy-1-(1H-indazol-6-yl)-6-methylpyridin-2(1H)-one

The title compound was prepared by a similar procedure described for4-hydroxy-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-one. Yield=12%; ¹HNMR (CD₃OD/400 MHz) δ8.12 (s, 1H), 7.90 (d, 1H, J=8.0 Hz), 7.42 (s, 1H),6.94 (d, 1H, J=8.8 Hz) 6.08 (br s, 1H), 5.81 (d, 1H, J=2.4 Hz), and 1.96(s, 3H); ES-HRMS m/z 242.0946 (M+H calcd for C₁₃H₁₂N₃O₂ requires242.0924).

Step 2

The title was prepared by a similar procedure described for3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indazol-5-yl)-6-methylpyridin-2(1H)-one.¹H NMR (CD₃OD/400 MHz) δ8.14 (s, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.61 (m1H), 7.46 (s, 1H), 7.04 (m, 2H), 6.98 (m, 1H) 6.62 (s, 1H), 5.36 (s,2H), and 2.06 (s, 3H); ¹⁹F NMR (CD₃OD/400 MHz)-111.62 (m) and −116.03(m); ES-HRMS m/z 446.0302 (M+H calcd for C₁₃H₁₂N₃O₂ requires 446.0310).

Example 643

methyl2-{[(3-bromo-6-methyl-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamateStep 1: Preparation of methyl3-[4-[(2-cyano-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

To a cooled (0° C.) solution of 2-(bromomethyl)-5-fluorobenzonitrile(4.31 g, 20.1 mmol) and methyl3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (5.00 g,18.3 mmol) in DMF (20 mL) was added K₂CO₃ (3.00 g, 22.0 mmol). Thereaction was allowed to warm to RT and stirred overnight. Additional2-(bromomethyl)-5-fluorobenzonitrile (0.39 g, 1.83 mmol) and K₂CO₃ (0.25g, 1.83 mmol) were added and the reaction heated at 60° C. for 2 h.Solvent removed by distillation. Reaction neutralized with 5% citricacid (50 mL). Organic products were extracted in DCM (3×25 mL), driedover Na₂SO₄, filtered, and concentrated to a thick dark brown oil.Purified by silica gel flash column chromatography using EtOAc as theeluent to give the product as a brown solid, dried in vacuo (6.18 g,76%). ¹H NMR (CD₃OD/400 MHz) δ8.03 (m, 1H), 7.76 (m, 2H), 7.66 (m, 1H),7.52 (m, 2H), 6.24 (s, 1H), 6.09 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H),2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 407.1408 (M+H calculated forC₂₃H₂₀FN₂O₄ requires 407.1402).

Step 2: Preparation of methyl3-[4-([2-(aminomethyl)-4-fluorobenzyl]oxy)-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoatetrifluoroacetate

To a cooled (0° C.) solution of methyl3-[4-[(2-cyano-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate(from Step 1) (0.510 g, 1.25 mmol) in THF (5 mL) was added dropwiseBH₃THF (2.51 mL, 2.51 mmol). The reaction was then stirred at RT for 2.5h. Reaction cooled (0° C.), quenched by the slow addition of MeOH,concentrated, and purified by preparatory HPLC. The product was isolatedby freeze-drying and evaporation of the solvent to give a white solid,dried in vacuo (0.39 g, 76%). ¹H NMR (CD₃OD/400 MHz) 68.04 (m, 1H), 7.75(s, 1H), 7.63 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.32 (m, 1H), 7.24 (m,1H), 6.25 (s, 1H), 6.12 (s, 1H), 5.23 (s, 2H), 4.25 (s, 2H), 3.90 (s,3H), 2.11 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 411.1691 (M+H calculated forC₂₃H₂₄FN₂O₄ requires 411.1715).

Step 3: Preparation of methyl3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

To a cooled (0° C.) solution of methyl3-[4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoatetrifluoroacetate (from Step 2) (0.50 g, 0.95 mmol) in DMA (4 mL) wasadded 4-methylmorpholine (0.21 mL, 1.9 mmol) and methyl chloroformate(0.08 mL, 1.0 mmol). Reaction was stirred at RT for 1 h. Solvent removedby distillation. Crude product purified by preparatory HPLC.Acetonitrile was evaporated and the solution washed with 5% NaHCO₃ (30mL) and extracted in DCM (3×25 mL). The organic extracts were dried overNa₂SO₄, filtered, and concentrated to a white solid, dried in vacuo(0.36 g, 81%). ¹H NMR (CD₃OD/400 MHz) δ8.03 (m, 1H), 7.77 (s, 1H), 7.53(d, 1H, J=7.6 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s,1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H), 3.65 (s,3H), 2.12 (s, 3H), 1.89 (s, 3H). ESHRMS m/z 469.1767 (M+H calculated forC₂₅H₂₆FN₂O₆ requires 469.1769).

Step 4: Preparation of3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

To methyl3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate(from Step 3) (0.17 g, 0.36 mmol) was added 1.5 N NaOH solution in 1:1MeOH:water (0.39 mL, 0.59 mmol). The reaction mixture was stirred at 60°C. for 2.5 h. The solution was cooled (0° C.), neutralized by the slowaddition of 5% citric acid, and organic products extracted in DCM. Awhite solid suspended in the organic layer was filtered, washed with DCMand water, dried in vacuo, and found to be the desired product (0.090 g,55%). ¹H NMR (CD₃OD/400 MHz) δ8.03 (m, 1H), 7.75 (s, 1H), 7.52 (d, 1H,J=8.0 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08(s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.12 (s, 3H), 1.90(s, 3H). ESHRMS m/z 455.1632 (M+H calculated for C₂₄H₂₄FN₂O₆ requires455.1613).

Step 5: Preparation of3-[3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

NBS (0.69 g, 3.85 mmol) was added to a solution of3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5 h,solvent removed on rotary evaporator. Solid dissolved in EtOAc andhexane added, resulting in a solid precipitate. Solid filtered. Solidsubsequently dissolved in DCM and washed with water. Organic layer driedover Na₂SO₄, filtered, and concentrated. Pale yellow solid dried invacuo (1.47 g, 72%). ¹H NMR (CD₃OD/400 MHz) δ8.04 (m, 1H), 7.77 (s, 1H),7.54 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H),4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). ESHRMS m/z533.0700 and 535.0677 (M+H calculated for C₂₄H₂₃BrFN₂O₆ requires533.0718 and 535.0701).

Step 6: Preparation of the Title Compound

To a cooled (−10° C.) solution of3-[3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (0.07 g, 0.13 mmol) in DMF (2.0 mL) was added isobutylchloroformate (0.02 mL, 0.16 mmol) and 4-methylmorpholine (0.02 mL, 0.16mmol). After 15 min, 2.0M methylamine in THF (0.01 mL, 0.20 mmol) wasadded. Solvent removed by distillation after 30 min. Crude productpurified by preparatory HPLC. Acetonitrile was evaporated and thesolution washed with 5% NaHCO₃ (30 mL) and extracted in DCM (3×25 mL).The organic extracts were dried over Na₂SO₄, filtered, concentrated, anddried in vacuo to give a white foam, (0.061 g, 86%). ¹H NMR (CD₃OD/400MHz) δ7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s,1H), 5.40 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s,3H), 1.99 (s, 3H). ESHRMS m/z 546.0987 and 548.1018 (M+H calculated forC₂₅H₂₆BrFN₃O₅ requires 546.1034 and 548.1018).

Example 644

methyl2-({[3-bromo-1-(5-{[(2-hydroxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

The title compound was prepared using a procedure similar to that usedin the preparation of Example 643. ¹H NMR (CD₃OD/400 MHz) δ7.88 (m, 1H),7.61 (s, 1H), 7.53 (m, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.68 (s, 1H),5.41 (s, 2H), 4.43 (s, 2H), 3.68 (t, 2H, J=5.6 Hz), 3.64 (s, 3H), 3.48(t, 2H, J=5.6 Hz), 2.08 (s, 3H), 2.00 (s, 3H). ESHRMS m/z 576.1101 and578.1072 (M+H calculated for C₂₆H₂₈BrFN₃O₆ requires 576.1140 and578.1124).

Example 645

methyl2-({[3-bromo-1-(5-{[(2-hydroxy-2-methylpropyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

The title compound was prepared using a procedure similar to that usedin the preparation of Example 643. ¹H NMR (CD₃OD/400 MHz) δ7.89 (m, 1H),7.63 (s, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.69 (s, 1H),5.41 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 3.38 (s, 2H), 2.09 (s, 3H),2.01 (d, 6H, J=3.2 Hz), 1.21 (s, 3H). ESHRMS m/z 604.1412 and 606.1418(M+H calculated for C₂₈H₃₂BrFN₃O₆ requires 604.1453 and 606.1438).

Example 646

methyl2-({([3-bromo-1-(5-{[(2-methoxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

The title compound was prepared using a procedure similar to that usedin the preparation of Example 643. ¹H NMR (CD₃OD/400 MHz) δ7.87 (m, 1H),7.59 (s, 1H), 7.53 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H),5.41 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 3.54 (s, 4H), 3.35 (s, 3H),2.08 (s, 3H), 2.00 (s, 3H). ESHRMS m/z 590.1267 and 592.1219 (M+Hcalculated for C₂₇H₃₀BrFN₃O₆ requires 590.1297 and 592.1281).

Example 647

methyl2-[({1-[5-(aminocarbonyl)-2-methylphenyl]-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl}oxy)methyl]-5-fluorobenzylcarbamate

The title compound was prepared using a procedure similar to that usedin the preparation of Example 643. ¹H NMR (CD₃OD/400 MHz) δ7.91 (m, 1H),7.64 (s, 1H), 7.54 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H),5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 2.00 (s, 3H).ESHRMS m/z 532.0836 and 534.0787 (M+H calculated for C₂₄H₂₄BrFN₃O₅requires 532.0878 and 534.0861).

Example 648

N-[2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]-N′-phenylurea

To a cooled (0° C.) solution of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.25 g, 0.48 mmol) in DMA (2.0 mL) was added4-methylmorpholine (0.06 mL, 0.53 mmol) and phenyl isocyanate (0.06 mL,0.53 mmol). The reaction was stirred at RT for 1.5 h. Solvent distilledand crude product purified by preparatory HPLC. Acetonitrile wasevaporated and the solution washed with 5% NaHCO₃ (30 mL) and extractedin DCM (3×25 mL). The organic extracts were dried over Na₂SO₄, filtered,and concentrated to a white solid, dried in vacuo (0.18 g, 71%). ¹H NMR(CD₃OD/400 MHz) δ7.60 (m, 1H), 7.54 (m, 1H), 7.33 (d, 2H, J=7.6 Hz),7.22 (m, 5H), 7.06 (m, 1H), 6.95 (t, 1H, J=7.2 Hz), 6.73 (s, 1H), 5.44(s, 2H), 4.53 (s, 2H), 2.07 (s, 3H). ESHRMS m/z 528.1304 (M+H calculatedfor C₂₇H₂₂ClF₃N₃O₃ requires 528.1296).

Example 649

thien-3-ylmethyl2-({[3-chloro-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

To a cooled (0° C.) solution of4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-onetrifluoroacetate (0.26 g, 0.50 mmol) and 1,1-carbonyldiimidazole (0.10g, 0.60 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL,0.55 mmol). After 1 h at RT, 3-thiophenemethanol (0.09 mL, 0.99 mmol)was added. No product was observed after 2 h at RT. NaH (0.01 g, 0.50mmol) was added and the reaction stirred at 60° C. Reaction was completeafter 20 min. The reaction mixture was cooled (0° C.) and acetic acidadded to quench the reaction. Solvent removed by distillation. Crudeproduct purified by preparatory HPLC. Acetonitrile was evaporated andthe solution washed with 5% NaHCO₃ (30 mL) and extracted in DCM (3×25mL). The organic extracts were dried over Na₂SO₄, filtered, andconcentrated to a white foam, dried in vacuo (0.20 g, 73%). ¹H NMR(CD₃OD/400 MHz) δ7.61 (m, 1H), 7.52 (m, 1H), 7.34 (s, 2H), 7.23 (t, 3H,J=8.4 Hz), 7.10 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.43(s, 2H), 2.10 (s, 3H). ESHRMS m/z 549.0858 (M+H calculated forC₂₆H₂₁ClF₃N₂O₄S requires 549.0857).

Example 650

ethyl2-{[(3-bromo-6-methyl-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamateStep 1: Preparation of methyl3-[4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

Prepared using a procedure similar to that used in the preparation ofmethyl3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate.¹H NMR (CD₃OD/400 MHz) δ8.03 (m, 1H), 7.76 (s, 1H), 7.53 (d, 1H, J=8.0Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s,1H), 5.18 (s, 2H), 4.38 (s, 2H), 4.08 (q, 2H, J=6.8 Hz), 3.89 (s, 3H),2.12 (s, 3H), 1.89 (s, 3H), 1.23 (t, 3H, J=6.8 Hz). ESHRMS m/z 483.1900(M+H calculated for C₂₆H₂₈FN₂O₆ requires 483.1926).

Step 2: Preparation of3-[4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

Prepared using a procedure similar to that used in the preparation of3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid. ¹H NMR (CD₃OD/400 MHz) δ8.03 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H),7.11 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H),4.38 (s, 2H), 4.08 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 1.90 (s, 3H), 1.23(L, 3H, J=7.2 Hz). ESHRMS m/z 469.1738 (M+H calculated for C₂₅H₂₆FN₂O₆requires 469.1769).

Step 3: Preparation of3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

Prepared using a procedure similar to that used in Step 5 of thesynthesis of Example 643. ¹H NMR (CD₃OD/400 MHz) δ8.04 (m, 1H), 7.76 (s,1H), 7.55 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s,2H), 4.43 (s, 2H), 4.07 (m, 2H), 2.09 (s, 3H), 1.99 (s, 3H), 1.22 (t,3H, J=7.2 Hz). ESHRMS m/z 547.0842 and 549.0818 (M+H calculated forC₂₅H₂₅BrFN₂O₆ requires 547.0875 and 549.0858).

Step 4

Prepared using a procedure similar to that used in the preparation ofExample 643. ¹H NMR (CD₃OD/400 MHz) δ7.85 (m, 1H), 7.54 (m, 3H), 7.13(m, 1H), 7.04 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43 (s, 2H), 4.07(q, 2H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.23 (t, 3H, J=7.2Hz). ESHRMS m/z 560.1215 and 562.1193 (M+H calculated for C₂₆H₂₈BrFN₃O₅requires 560.1191 and 562.1175).

Example 651

3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamideStep 1: Preparation of methyl3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

To a cooled (0° C.) solution of methyl3-[4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoatetrifluoroacetate( ) (1.13 g, 2.16 mmol) and 1,1-carbonyldiimidazole(0.42 g, 2.59 mmol) in DMA (8.0 mL) was added 4-methylmorpholine (0.36mL, 3.2 mmol). Reaction was stirred at RT for 2 h. DMA removed bydistillation. Crude product purified by preparatory HPLC. Acetonitrilewas evaporated and the solution washed with 5% NaHCO₃ (30 mL) andextracted in DCM (3×25 mL). The organic extracts were dried over Na₂SO₄,filtered, concentrated, and dried in vacuo (0.78 g, 73%). ¹H NMR(CD₃OD/400 MHz) δ8.03 (m, 1H), 7.76 (s, 1H), 7.53 (d, 1H, J=8.0 Hz),7.46 (m, 1H), 7.12 (m, 1H), 7.01 (m, 1H), 6.22 (s, 1H), 6.08 (s, 1H),5.19 (s, 2H), 4.44 (s, 2H), 3.89 (s, 3H), 2.48 (m, 1H), 2.12 (s, 3H),1.89 (s, 3H), 0.70 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 494.2076 (M+Hcalculated for C₂₇H₂₉FN₃O₅ requires 494.2086).

Step 2: Preparation of3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

Prepared using a procedure similar to that used in the preparation of3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid. ¹H NMR (CD₃OD/400 MHz) δ8.02 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H),7.12 (m, 1H), 7.01 (m, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 5.19 (s, 2H),4.44 (s, 2H), 2.48 (m, 1H), 2.11 (s, 3H), 1.90 (s, 3H), 0.69 (m, 2H),0.47 (m, 2H). ESHRMS m/z 480.1921 (M+H calculated for C₂₆H₂₇FN₃O₅requires 480.1929).

Step 3: Preparation of3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

Prepared using a procedure similar to that used in Step 5 of thesynthesis of Example 643. ¹H NMR (DMSO-d₆/400 MHz) δ7.92 (m, 1H), 7.67(s, 1H), 7.54 (m, 2H), 7.12 (m, 2H), 6.71 (s, 1H), 5.37 (s, 2H), 4.31(d, 2H, J=6.4 Hz), 2.40 (m, 1H), 2.00 (s, 3H), 1.88 (s, 3H), 0.56 (m,2H), 0.33 (m, 2H). ESHRMS m/z 558.0988 and 560.0981 (M+H calculated forC₂₆H₂₆BrFN₃O₅ requires 558.1034 and 560.1018).

Step 4

Prepared using a procedure similar to that used in the preparation ofExample 643. ¹H NMR (CD₃OD/400 MHz) δ7.85 (m, 1H), 7.54 (m, 3H), 7.14(m, 1H), 7.03 (m, 1H), 6.69 (s, 1H), 5.41 (s, 2H), 4.48 (s, 2H), 2.89(s, 3H), 2.48 (m, 1H), 2.08 (s, 3H), 1.99 (s, 2H), 0.70 (m, 2H), 0.47(m, 2H). ESHRMS m/z 571.1348 and 573.1355 (M+H calculated forC₂₇H₂₉BrFN₄O₄ requires 571.1351 and 573.1335).

Example 652

-   3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic    acid

Step 1: Preparation of ethyl (5-fluoro-2-methylphenoxy)acetate

To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) andethylbromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K₂CO₃(1.10 g, 7 93 mmol). After 30 min at RT, DMF was removed bydistillation. The crude product was washed with 5% citric acid (30 mL)and water (30 mL), extracted in DCM (3×20 mL), dried over Na₂SO₄,filtered, concentrated, and dried in vacuo. Desired product obtained asyellow oil (1.30 g, 77%). ¹H NMR (CD₃OD/400 MHz) δ7.09 (t, 1H, J=8.8Hz), 6.58 (m, 1H), 6.56 (m, 1H), 4.71 (s, 2H), 4.23 (q, 2H, J=7.2 Hz),2.18 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). ESHRMS m/z 212.0847 (M+Hcalculated for C₁₁H₁₃FO₃ requires 212.0849).

Step 2: Preparation of ethyl[2-(bromomethyl)-5-fluorophenoxy]acetate

A solution of ethyl (5-fluoro-2-methylphenoxy)acetate (from Step 1)(0.65 g, 3.06 mmol), NBS (0.65 g, 3.68 mmol), and benzoyl peroxide (0.05g, 0.21 mmol) in CCl4 (7.0 mL) were refluxed at 90° C. for 2.5 h.Additional NBS (0.16 g, 0.92 mmol) added, and reaction continuedovernight. Solid filtered and filtrate concentrated onto silica gel.Purified by flash column chromatography using hexane and 2.5%EtOAc/hexane as eluent. Product obtained as yellow liquid (0.27 g, 30%).¹H NMR (CD₃OD/400 MHz) δ7.37 (m, 1H), 6.69 (m, 2H), 4.80 (s, 2H), 4.60(s, 2H), 4.23 (q, 2H, J=7.2 Hz), 1.27 (t, 3H, J=7.2 Hz).

Step 3: Preparation ofethyl[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetate

To a solution of ethyl[2-(bromomethyl)-5-fluorophenoxy]acetate (fromStep 2) (0.59 g, 2.03 mmol) and3-bromo-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.61g, 1.93 mmol) in DMF (3.0 mL) was added K₂CO₃ (0.34 g, 2.43 mmol). After2 h at RT, DMF was removed by distillation. The crude product was washedwith 5% citric acid, extracted in DCM, dried over Na₂SO₄, filtered, andconcentrated onto silica gel. Purified by flash column chromatographyusing 50% EtOAc/hexane as the eluent. Obtained product as a pale yellowsolid (0.45 g, 42%). ¹H NMR (CD₃OD/400 MHz) δ7.21 (q, 3H, J=8.4 Hz),6.80 (m, 2H), 6.69 (s, 1H), 6.15 (s, 1H), 5.40 (s, 2H), 4.84 (s, 2H),4.23 (q, 2H, J=6.8 Hz), 2.08 (s, 3H), 1.26 (t, 3H, J=6.8 Hz). ESHRMS m/z526.0446 and 528.0414 (M+H calculated for C₂₃H₂₀BrF₃NO₅ requires526.0471 and 528.0454).

Step 4: Preparation of[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]aceticacid

A solution ofethyl[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetate(from Step 3) (0.62 g, 1.18 mmol), 1.5 N NaOH solution in 1:1 MeOH:water(1.2 mL, 1.77 mmol), and THF (1.2 mL) were refluxed at 60° C. for 1 h.The solution was concentrated on a rotary evaporator, cooled, and 5%citric acid added. The solid precipitate was filtered and dried invacuo. Product obtained as a pale yellow solid (0.35 g, 60%). ¹H NMR(CD₃OD/400 MHz) δ7.59 (m, 1H), 7.49 (m, 1H), 7.22 (m, 2H), 6.75 (m, 2H),6.72 (s, 1H), 5.43 (s, 2H), 4.66 (s, 2H), 2.07 (s, 3H). ESHRMS m/z498.0143 and 500.0186 (M+H calculated for C₂₁H₁₆BrF₃NO₅ requires498.0158 and 500.0141).

Step 5: Preparation of2-[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]-N-ethylacetamide

To a cooled (−10° C.) solution of[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]aceticacid (from Step 4) (0.15 g, 0.30 mmol) in DMA (2.0 mL) was added4-methylmorpholine (0.04 mL, 0.36 mmol) and isobutyl chloroformate (0.05mL, 0.36 mmol). Ethylamine (0.04 mL, 0.45 mmol) was added after 20minutes. DMF removed by distillation after 1 h. Crude product purifiedby preparatory HPLC. Acetonitrile was evaporated and the solution washedwith 5% NaHCO₃ (30 mL) and extracted in DCM (3×25 mL). The organicextracts were dried over Na₂SO₄, filtered, concentrated, and dried invacuo to give a white solid (0.080 g, 51%). ¹H NMR (CD₃OD/400 MHz) δ7.60(m, 1H), 7.53 (t, 1H, J=8.0 Hz), 7.23 (t, 2H, J=8.4 Hz), 6.82 (m, 2H),6.71 (s, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 3.31 (q, 2H, J=6.4 Hz), 2.10(s, 3H), 1.09 (t, 3H, J=7.2 Hz). ESHRMS m/z 525.0616 and 527.0568 (M+Hcalculated for C₂₃H₂₁BrF₃N₂O₄ requires 525.0631 and 527.0614).

Example 653

methyl3-[6-[(acetyloxy)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-4-methylbenzoateStep 1: Preparation of3-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-oxopropyl acetate

A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (20 g, 141 mmol) indry THF (400 mL) was cooled to −78° C. To this solution was slowly addeda LiHMDS (1M-THF, 160 mL, 160 mmol). The resulting solution wasmaintained at −78° C. with stirring for 30 min. To the reaction mixturewas added acetoxy acetylchloride (17 mL, 160 mmol) and the resultingmixture was maintained at −78° C. for at 1 h. The reaction was thenallowed to slowly warm to rt and stir for an additional 1 h. Thereaction was then quenched with addition of a 1N solution of ammoniumchloride. The layers were separated and the aqueous layer was extractedwith ethyl acetate (5×). The organics were combined, dried, andconcentrated in vacuo. The crude product was purified using a mediumpressure liquid chromatography biotage system. Elution withhexanes-ethyl acetate (3:1) gave 13.1 g (38%) of a red-brown oil. Theproduct looks clean by NMR. ¹H NMR (300 MHz, CDCl₃) δ 5.42 (s, 1H), 4.75(s, 2H), 3.41 (s, 2H), 2.22 (s, 3H), 1.75 (s, 6H).

Step 2: Preparation of methyl3-[6-[(acetyloxy)methyl]-4-hydroxy-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

To a 100 mL RBF containing methyl 3-amino, 4-methylbenzoate (1.65 g, 10mmol) was added the enone from Step 1-(2.6 g, 10.7 mmol). The mixturewas then dissolved in toluene (40 mL), fitted with a reflux condenser,and placed in an oil bath preset to 115° C. The mixture was heated toreflux for 1.5 h. The reaction flask was removed from the oil bath and acatalytic amount of TFA (5-6 drops) was added. The reaction was placedback in the oil bath and heated to reflux for an additional 2 h. Thereaction was then allowed to cool to 0° C. The toluene was then removedunder vacuum to give a thick brown residue. The residue was thendissolved in acetonitrile (10-15 mL) and allowed to stand. After 20-30min a precipitate results which was filtered and washed with diethylether. After drying, an off-white solid (1.9 g, 57% yield) was obtained.¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (dd, J=7.8, 1.5 Hz, 1H), 7.73 (s, 1H),7.54 (d, J=8.1 Hz, 1H), 6.19 (s, 1H), 5.73-5.71 (m, 1H), 4.47 (AB quar,J=10.5 Hz, 2H), 3.87 (s, 3H), 2.09 (s, 3H), 1.91 (s, 3H). ES-HRMS m/z332.1096 (M+H calcd for C₁₇H₁₈NO₆ requires 332.1129).

Step 3: Preparation of methyl3-[6-[(acetyloxy)methyl]-3-bromo-4-hydroxy-2-oxopyridin-1(2H)-yl]-4-methylbenzoate

To a slurry of the phenol (2.5 g, 7.5 mmol) in dry acetonitrile (50 mL),at rt, was added n-bromosuccinimide (1.33 g, 7.5 mmol). The resultinghomogeneous mixture was stirred at rt for 3 h. The resulting precipitatewas filtered and washed sequentially with acetonitrile and the diethylether. The product was dried in a vacuum oven to yield an off-whitesolid (2.5 g, 81%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.97 (dd,J=7.8, 1.5 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 6.38(s, 1H), 4.49 (AB quar, J=13.8 Hz, 2H), 3.87 (s, 3H), 2.08 (s, 3H), 1.92(s, 3H). ES-HRMS m/z 410.0225 (M+H calcd for C₁₇H₁₇NBrO₆ requires410.0234).

Step 4: Preparation of the title compound. To a solution of the abovephenol (2.5 g, 6.0 mmol) in dry DMF (25 mL) was added solid potassiumcarbonate (804 mg, 6.0 mmol). To this mixture was then added, viasyringe, 2,4-difluorobenzyl bromide (783 μL, 6.0 mmol). The resultingmixture was allowed to stir at rt overnight. The reaction was thenpoured into ice water and stirred vigorously. The resulting precipitatewas filtered and washed sequentially with water and diethyl ether. Thesolid was dried in a vacuum oven to yield an off-white solid (3.3 g,99%). ¹H NMR (400 MHz, DMSO-D₆) δ 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.83 (d,J=1.6 Hz, 1H), 7.71 (q, J=8.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.37 (dt,J=10.4, 2.4 Hz, 1H), 7.21 (dt, J=8.4, 2.0 Hz, 1H), 6.90 (s, 1H), 5.40(s, 2H), 4.57 (AB quar, J=13.6 Hz, 2H), 3.86 (s, 3H), 2.07 (s, 3H), 1.90(s, 3H). ES-HRMS m/z 536.0484 (M+H calcd for C₂₄H₂₁NF₂BrO₆ requires536.0515).

Example 654

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid

To a stirred suspension, at rt, of the Example 643 (2.0 g, 3.7 mmol) inTHF (10 mL) was added a solution of 2.5N NaOH (3 mL, 7.5 mmol). Theresulting homogeneous solution was stirred for 2 h. The reaction wasjudged complete and 1N HCl was added dropwise until a pH −4 wasobtained. The reaction was then diluted with CH₂Cl₂ (10 mL). Theresulting precipitate was filtered with additional washing from CH₂Cl₂.The solid was dried in a vacuum oven to yield a pure white solid (1.8 g,99%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (dd, J=7.8, 1.8 Hz, 1H),7.74-7.66 (m, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.37 (dq, J=7.8, 2.7 Hz, 1H),7.24-7.17 (m, 1H), 6.72 (s, 1H), 5.39 (s, 2H), 3.83 (AB quar, J=15.6 Hz,2H), 2.02 (s, 3H). ES-HRMS m/z 480.0253 (M+H calcd for C₂₁H₁₇NF₂BrO₅requires 480.0253).

Example 655

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide

To a slurry of Example 654 (500 mg, 1.04 mmol) in anhydrous CH₂Cl₂ wasadded Et₃N (218 μL, 1.56 mmol) and the resulting homogeneous mixture wasstirred at rt. To this mixture was then added ethanolamine (70 μL, 1.14mmol) via syringe. HOBt (155 mg, 1.14 mmol) was then added followed byaddition of EDC (217 mg, 1.14 mmol). The reaction was allowed to stirovernight at rt. The reaction was quenched by addition of a solution of1N NH₄Cl. The biphasic mixture was separated and the aqueous layer wasextracted with CH₂Cl₂ (4×). The organics were combined, dried, andconcentrated in vacuo. The resulting residue was purified by flashchromatography on a 16 g Michele-Miller column. Elution with CH₂Cl₂-MeOH(10:1→12:1) resulted in obtaining the desired product as a viscous oil.The oil was then dissolved in a CH₃CN-Et₂O combination. After 5-10minutes, a precipitate resulted which upon filtration and drying yieldeda pure white solid (210 mg, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (t,J=5.2 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.50 (d,J=8.4 Hz, 1H), 7.37 (dq, J=9.6, 2.4 Hz, 1H), 7.20 (dq, J=7.6, 1.6 Hz,1H), 6.71 (s, 1H), 5.68 (t, J=5.6 Hz, —OH), 5.40 (s, 2H), 4.73 (t, J=5.6Hz, —OH), 4.02 (dd, J=16.4, 5.6 Hz, 1H), 3.70 (dd, J=16.4, 5.6 Hz, 1H),3.52-3.48 (m, 2H), 3.39-3.25 (m, 2H), 2.00 (s, 3H). ES-HRMS m/z 523.0674(M+H calcd for C₂₃H₂₂N₂F₂BrO₅ requires 523.0675).

Example 656

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide

The titled compound was prepared from the acid Example 654 (550 mg, 1.07mmol) in a similar manner to the amide described above using EDC (245mg, 1.28 mmol), HOBt (171 μL, 1.28 mmol), Et₃N (225 mL, 1.6 mmol), and2.0M MeNH₂-THF (1.2 μL, 2.48 mmol). Following work-up with 1N NH₄Cl theproduct was precipitated out of the biphasic mixture after dilution withadditional CH₂Cl₂ to give a white solid (250 mg, 51% yield). %). ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (quar, J=4.5 Hz, 1H), 7.88 (dd, J=8.1, 1.8 Hz,1H), 7.72 (app quar, J=6.6 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.52 (d,J=8.1 Hz, 1H), 7.37 (dt, J=10.2, 2.4 Hz, 1H), 7.20 (app dt, J=8.4, 1.8Hz, 1H), 6.74 (s, 1H), 5.71 (t, J=5.4 Hz, 1H), 5.42 (s, 2H), 4.03 (dd,J=13.8, 5.1 Hz, 1H), 3.72 (dd, J=16.4, 5.1 Hz, 1H), 2.78 (d, J=4.5 Hz,3H), 2.02 (s, 3H). ES-HRMS m/z 493.0575 (M+H calcd for C₂₂H₂₀N₂F₂BrO₄requires 493.0569).

Example 657

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-4-methylbenzamide

To a stirred suspension, at rt, of the carboxylic acid Example 654 (400mg, 0.80 mmol) in anhydrous THF (4 mL) was added 4-methylmorpholine (274μL, 2.5 mmol). To the resulting heterogeneous solution was then added2-Chloro-4,6-dimethyltriazine (170 mg, 1.0 mmol) and the mixture wasallowed to stir for 1 h at rt Ammonium hydroxide solution (28-32%, 2 mL)was then added to the reaction and it was allowed to stir at rtovernight. The reaction was then worked up by diluting with H₂O (2-3 mL)and stirring vigorously. The resulting precipitate was filtered andwashed with H₂O and then diethyl ether. After drying with a vacuum ovenan off-white solid (140 mg, 32%) was obtained. %). ¹H NMR (300 MHz,DMSO-d₆) δ 7.99-7.80 (m, 2H), 7.76 (m, 3H), 7.52 (d, J=8.1 Hz, 1H),7.43-7.39 (m, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.43-7.36 (m, 2H), 7.20 (dt,J=8.7, 1.8 Hz, 1H), 6.74 (s, 1H), 5.41 (s, 2H), 4.02-3.62 (m, 2H), 2.03(s, 3H). ES-HRMS m/z 479.0411 (M+H calcd for C₂₁H₁₈N₂F₂BrO₄ requires479.0413).

Example 658

(5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2-methyl-5-[(methylamino)carbonyl]phenyl}-6-oxo-1,6-dihydropyridin-2-yl)methylacetate

To a solution of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide,(225 mg, 0.50 mmol) stirred in CH₁₂Cl₂ was added pyridine (55 μL, 0.69mmol). To the resulting homogeneous solution was then added aceticanhydride (47 μL, 0.51 mmol). The mixture was stirred at rt for 3 h.Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL,1.05 mmol) were then added and the reaction was allowed to stirovernight at rt. The reaction was then quenched with 1N NHCl₄ anddiluted with CH₂Cl₂. The layers were separated and the organic layer wasthen extracted with CH₂Cl₂ (3×). The organics were then combined, dried,and concentrated in vacuo. The residue was then triturated with Et₂O andfiltered to give (150 mg, 61%) an off-white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.48 (br s, 1H), 7.87 (app d, J=7.8 Hz, 1H), 7.74-7.69 (m,2H), 7.52 (d, J=7.5 Hz, 1H), 7.40 (app t, J=8.1 Hz, 1H), 7.28-7.19 (m,1H), 6.91 (s, 1H), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s,3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C₂₄H₂₂N₂F₂BrO₅requires 535.0675).

Example 659

(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-methylbut-2-enamide

Step 1,(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]but-2-enoicacid: The carboxylic acid compo was prepared by stirring the ester (900mg, 2.1 mmol) in THF (10 mL). To this solution was added 1N NaOH (1 mL)and the resulting mixture was stirred at rt. After 2 h, additional NaOH(1 mL) was added to the reaction and then allowed to stir at rtovernight. The THF was then concentrated under vacuum. The remainingaqueous layer was then acidified to pH-4 after which a white precipitateresulted. Filtration and drying under vacuum gave rise to a white solid(900 mg) that was used as in the next step.

The titled compound was prepared by stirring the above acid (480 mg,1.16 mmol) in CH₂Cl₂ at rt. To this mixture was added sequentially Et₃N(244 μL), HOBt (188 mg, 1.4 mmol), MeNH₂ (2.0M-THF, 700 mL, 1.4 mmol),and finally EDC (266 mg, 1.4 mmol). The homogeneous mixture was thenallowed to stir at rt overnight. The reaction was quenched with 1N HCl.The layers were separated and the aqueous layer was extracted withCH₂Cl₂ (4×). The organics were combined, dried, and concentrated invacuo. The crude residue was triturated in CH₃CN-Et₂O combination andfiltered to give a pure white solid (330 mg, 67%). ¹H-NMR (DMSO_(d6)/300MHz) δ 8.20-7.90 (m, 1H), 7.68 (q, J=8.4 hz, 1H); 7.37 (dt, J=10.2, 2.4Hz, 1H); 7.20 (dt, J=15.6, 4.2 Hz, 1H); 6.60 (s, 1H), 5.63 (d, J=15.6Hz, 1H), 5.31 (s, 2H), 4.81 (d, J=2.7 Hz, 2H), 3.33 (d, J=6.9 Hz, 1H),2.61 (d, J=4.8 Hz, 3H), 2.37 (s, 3H). ES-HRMS m/z 427.0493 (M+H calcdfor C₁₈H₁₈BrF₂N₂O₃=427.0463).

Example 660

methyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoate

Step 1: To a room temperature suspension of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (330.1 mg,1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (1.6 mL) was addedmethyl-5-chloromethyl-2-furate (400 mg, 2.30 mmol). The resultingsuspension was stirred and heated to 68° C. for 8 hours until completeconsumption of starting material by LCMS analysis. The reaction mixturewas then diluted with ammonium chloride (saturated aqueous solution, 10mL) and water (100 mL). This resulting emulsion was then extracted withethyl acetate (3×300 mL). The resulting organic extract was separated,Na₂SO₄ dried, and concentrated. The resulting dark residue was subjectedto SiO₂ chromatography with ethyl acetate/hexanes (3:7) to furnish asolid. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (app q, J=8.2 Hz, 1H), 7.07 (d,J=3.5 Hz, 1H), 6.93 (app dt, J=8.4, 1.5 Hz, 1H), 6.84 (app ddd, J=10.2,8.7, 2.4 Hz, 1H), 6.53 (d, J=3.4 Hz, 1H), 6.00 (s, 1H), 5.27 (s, 2H),5.18 (s, 2H), 3.85 (s, 3H), 2.54 (s, 3H); LC/MS C-18 column, t_(r)=2.64minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min withdetection 254 nm, at 50° C.). ES-MS m/z 468 (M+H). ES-HRMS m/z 468.0276(M+H calcd for C₂₀H₁₇BrF₂NO₅ requires 468.0253).

Example 661

3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-(hydroxymethyl)-N-methylbenzamideStep 1: Preparation of2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoicacid

To a room temperature solution of methyl2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate(1.05 g, 2.02 mmol) in THF (10.0 mL) was added dropwise an aqueoussolution of sodium hydroxide (3.0 M, 3.5 mL, 10 mmol). The reaction wasthen heated to 60° C. for 8.0 hours. The resulting suspension was thendiluted with 500 mL of ethyl acetate and neutralized with an aqueoussolution of hydrochloric acid (2.0 N, 5.0 mL, 10 mmol). The resultingbiphasic solution was separated and the resulting aqueous layer wasfurther extracted with ethyl acetate (2×200 mL). The resulting combinedorganic extracts were Na₂SO₄ dried, filtered and concentrated in vacuoto a volume of 50 mL. At this time a white solid began to form and theresulting solid suspension was allowed to sit until precipitationappeared to stop (approximately 1.0 hour). The precipitate was collectedand dried in vacuo (1.0 mm Hg) to furnish the solid acid as anintermediate (806 mg, 78%). ¹H NMR (400 MHz, d₇-DMF) δ 13.19 (s, 1H),8.63 (app d, J=4.5 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.0, 1.6Hz, 1H), 7.71-7.67 (m, 2H), 7.34 (app dt, J=9.6, 1.6 Hz, 1H), 7.16 (appdt, J=8.7, 1.8 Hz, 1H), 6.66 (s, 1H), 5.33 (s, 2H), 3.29 (s, 3H), 1.92(s, 3H); LC/MS C-18 column, t_(r)=2.15 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0344 (M+H calcd forC₂₂H₁₈BrF₂N₂O₅ requires 507.0362).

Step 2: Preparation of the title compound. To a 0° C. solution of2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoicacid (500 mg, 0.986 mmol) in THF (6.8 mL) was added dropwise a solutionof borane-dimethyl sulfide complex (THF solution, 2.0 M, 2.0 mL, 4.0mmol). The internal temperature of the reaction was never allowed toexceed 0° C. The resulting solution was maintained for 4.0 hours, atwhich time the cooling bath was removed and the reaction was maintainedat room temperature for an additional two hours. Next, a solution ofammonium chloride (saturated aqueous, 300 mL) was added. The resultingemulsion was extracted with ethyl acetate (3×300 mL) and the resultingorganic extracts were separated, Na₂SO₄ dried, and concentrated in vacuoto a residue that was subjected to SiO₂ chromatography with ethylacetate/hexanes (6:4) to furnish a solid (392 mg, 81%). ¹H NMR (400 MHz,d₄-MeOH) δ 7.96 (dd, J=8.0, 1.9 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.65(app q, J=8.0 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.05 (app t, J=8.5 Hz,2H), 6.64 (s, 1H), 5.36 (s, 2H), 4.35 (AB-q, J=14.1 Hz, Δ=60.8 Hz, 2H),2.90 (s, 3H), 2.03 (s, 3H); LC/MS C-18 column, t_(r)=2.16 minutes (5 to95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm,at 50° C.). ES-MS m/z 493 (M+H). ES-HRMS m/z 493.0590 (M+H calcd forC₂₂H₂₀BrF₂N₂O₄ requires 493.0596).

Example 662

2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,N′-dimethylterephthalamide

Step 1: To a room temperature solution of2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoicacid (500 mg, 0.986 mmol) in DMF (5.0 mL) was added1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HCl,350.0 mg, 1.83 mmol) and 1-hydroxy-benzotriazole (HOBT, 100.0 mg, 0.74mmol) sequentially. To this resulting suspension was then added asolution of methylamine (2.0 M THF, 1.0 mL, 2.0 mmol). The reaction wasstirred for 16.0 hours, at which time the reaction was diluted withethyl acetate (600 mL). The mixture was washed with (3×200 mL) of waterand the organic extract was separated, Na₂SO₄ dried, and concentrated invacuo to a volume of approximately 60 mL. At this time a solidprecipitate formed and was collected to furnish (289 mg, 56%). ¹H NMR(300 MHz, d₄-MeOH) δ 8.06 (br d, J=8.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H),7.73 (s, 1H), 7.70 (app q, J=7.4 Hz, 1H), 7.09 (app t, J=8.0 Hz, 2H),6.65 (s, 1H), 5.39 (s, 2H), 2.96 (s, 3H), 2.79 (s, 3H), 2.13 (s, 3H);LC/MS C-18 column, t_(r)=2.13 minutes (5 to 95% acetonitrile/water over5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES MS m/z 520(M+H). ES-HRMS m/z 520.0700 (M+H calcd for C₂₃H₂₁BrF₂N₃O₄ requires520.0678).

Example 663

2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N-4-methylterephthalamide

Step 1: To a room temperature suspension of2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoicacid (302 mg, 0.595 mmol) in THF (1.8 mL) was added 2-chloro-4,6dimethoxy-1,3,5 triazine (140.5 mg, 0.800 mmol) and N-methyl morpholine(NMM, 184 mg, 1.824 mmol) sequentially. The resulting solution wasmatured for 2 hours and then a saturated aqueous solution of ammoniumhydroxide (0.60 mL) was added. The reaction was allowed to continue for1 additional hour at which time a precipitate formed which wascollected, washed with 20 mL of diethyl ether, and dried in vacuo tofurnish a solid (201 mg, 66%). ¹H NMR (400 MHz, d₆-DMSO) δ 8 59 (hr d,J=8.0, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J=9.0, 1H),7.69-7.64 (m, 2H), 7.39-7.31 (m, 1H), 7.19 (app t, J=8.0 Hz, 1H), 6.60(s, 1H), 5.31 (s, 2H), 3.85 (s, 1H), 2.78 (br d, J=8.0 Hz, 3H), 1.96 (s,3H); LC/MS C-18 column, t_(r)=2.20 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z506 (M+H). ES-HRMS m/z 506.0550 (M+H calcd for C₂₂H₁₉BrF₂N₃O₄ requires506.0522).

Example 664

methyl4-(aminocarbonyl)-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate

Step 1: To a room temperature solution of3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-(methoxycarbonyl)benzoicacid (3.01 g, 9.93 mmol) in DMF (20 mL) was added1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HCl, 2.00g, 10.4 mmol) and 1-hydroxy-benzotriazole (HOBT, 50.0 mg, 0.367 mmol)sequentially. To this resulting suspension was then added a solution ofammonia (0.5 M 1,4 dioxane, 30.0 mL, 15.0 mmol). The reaction wasstirred for 16.0 hours until complete consumption of starting materialwas seen by LCMS analysis. At this time the reaction vessel was placedon a roto-evaporator at 30 mm Hg vacuum and maintained at 30° C. for 30minutes to strip off any residual ammonia from the reaction mixture. Thereaction vessel was removed from the roto-evaporator and subsequentlycharged with solid N-bromosuccinimide (1.790 g, 10.06 mmol) and theresulting reddish solution was stirred for 3.0 hours. At this time thereaction was charged with K₂CO₃ (3.00 g, 21.7 mmol) and 2,4difluorobenzyl bromide (1.95 mL, 15.2 mmol). The resulting suspensionwas stirred for 16.0 hours. At this time the reaction suspension wasdiluted with water (400 mL) and extracted with ethyl acetate (3×300 mL).The organic extracts were separated, Na₂SO₄ dried, and concentrated to aresidue that was subjected to SiO₂ chromatography using ethylacetate/hexanes/methanol (6:3.5:0.5) to furnish an off white solid (1.09g, 21%). ¹H NMR (400 MHz, d₄-MeOH) δ 8.21 (dd, J=8.5, 1.5 Hz, 1H), 8.09(dd, J=7.6, 2.0 Hz, 1H), 7.78 (br s, 1H), 7.65 (app q, J=7.9 Hz, 1H),7.03 (app t, J=8.0 Hz, 2H), 6.63 (s, 1H), 5.37 (s, 2H), 3.75 (s, 3H),2.02 (s, 3H); LC/MS C-18 column, t_(r)=2.28 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0385 (M+H calcd forC₂₂H₁₈BrF₂N₂O₅ requires 507.0362).

Example 665

2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N¹,N¹,N⁴-trimethylterephthalamide

Step 1: To a room temperature solution of2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoicacid (300 mg, 0.591 mmol) in DMF (1.8 mL) was added1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HCl,190.0 mg, 1.0 mmol) and 1-hydroxy-benzotriazole (HOBT, 26.0 mg, 0.191mmol) sequentially. To this resulting suspension was then added asolution of dimethylamine (2.0 M THF, 0.50 mL, 1.0 mmol). The reactionwas stirred for 16.0 hours, at which time the reaction mixture wasdirectly applied to SiO₂ chromatography with ethyl acetate/hexanes (6:4)to furnish a solid (206 mg, 65%). ¹H NMR (400 MHz, d₄-MeOH) δ 8.01 (dd,J=8.2, 1.5 Hz, 1H), 7.73 (app d, J=8.1 Hz, 1H), 7.61 (app q, J=7.2 Hz,1H), 7.60 (app d, J=9.5 Hz, 1H), 7.04 (app t, J=8.0 Hz, 2H), 6.65 (s,1H), 5.32 (s, 2H), 3.64 (s, 3H), 2.92 (s, 6H), 2.13 (s, 3H); LC/MS C-18column, t_(r)=2.20 minutes (5 to 95% acetonitrile/water over 5 minutesat 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 534 (M+H).ES-HRMS m/z 534.0820 (M+H calcd for C₂₄H₂₃BrF₂N₃O₄ requires 534.0835).

Example 666

2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzylcarbamate

Step 1: To a room temperature solution of3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-(hydroxymethyl)-N-methylbenzamide(493 mg, 1.00 mmol) in methylene chloride (5.0 mL) was added a solutionof trichloroacetyl isocyanate (toluene, 0.53 M, 1.9 mL, 1.0 mmol). Theresulting solution was stirred for one hour until complete consumptionof starting material by LCMS analysis. The reaction mixture was thendirectly applied to Al₂O₃ (0.5 g of activity type I) and the slurry wasmatured for three hours. At this time, the Al₂O₃ plug was flushed withethyl acetate/methanol (95:5) and the resulting mother liquor wasconcentrated to a residue that was subjected to SiO₂ chromatographyusing ethyl acetate/hexanes/methanol (6:3.5:0.5) to furnish a whitesolid (396 mg, 74%). ¹H NMR (300 MHz, d₄-MeOH) δ 8.00 (dd, J=8.0, 1.7Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.09 (app t, J=8.5Hz, 2H), 6.69 (s, 1H), 5.40 (s, 2H), 4.85 (m, 2H), 2.90 (s, 3H), 2.10(s, 3H); LC/MS C-18 column, t_(r)=2.15 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 536 (M+H). ES-HRMS m/z 536.0617 (M+H calcd forC₂₃H₂₁BrF₂N₃O₅ requires 536.0627).

Example 667

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(1H)-oneStep 1: Preparation of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(1H)-one

To a room temperature solution of1-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(4.01 g, 9.06 mmol) in anhydrous THF (30 mL) was added, sequentially,tributyl(vinyl)tin (5.00 g, 15.7 mmol) andtetrakis(tripheylphosphine)palladium (1.00 g, 0.865 mmol) under an argonstream. The reaction vessel was then equipped with a reflux condenserand the reaction system purged with an argon flow. The resulting yellowsolution was heated to 68° C. and stirred under a positive pressure ofargon for 12.0 hours until complete disappearance of starting materialby LCMS analysis. The reaction mixture was diluted with 300 mL of brineand extracted with ethyl acetate (3×300 mL). The organic extracts wereseparated, Na₂SO₄ dried, and concentrated in vacuo and the resultingdark residue was subjected to SiO₂ chromatography with ethylacetate/hexanes (1:1) to furnish a yellowish solid (3.18 g, 90%). ¹H NMR(400 MHz, CDCl₃) δ 7.41 (app q, J=8.0 Hz, 1H), 7.08 (app d, J=8.3 Hz,2H), 6.90 (app t, J=7.2 Hz, 1H), 6.85 (app t, J=7.4 Hz, 1H), 6.63 (dd,J=17.5, 10.9 Hz, 1H), 5.96 (app d, 15.8 Hz, 1H), 5.94 (app d, J=15.8 Hz,1H), 5.79 (d, J=17.4 Hz, 1H), 5.43 (d, J=10.9 Hz, 1H), 5.01 (br s, 2H),1.99 (s, 3H); LC/MS C-18 column, t_(r)=2.93 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 390 (M+H). ES-HRMS m/z 390.1095 (M+H calcd forC₂₁H₁₆F₄NO₂ requires 390.1112).

Step 2: To a briskly stirred room temperature solution of4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(1H)-one(721 mg, 1.85 mmol) in methylene chloride (10 mL) was added solidN-bromosuccinimide (330 mg, 1.86 mmol) and the resulting reddishsolution was stirred for 10 minutes. At this time the reaction wasdiluted with ethyl acetate (100 mL) and washed with sodium sulfite (5%aqueous solution, 50 mL) The resulting organic extracts were Na₂SO₄dried, filtered, and concentrated in vacuo to approximately 50 mLvolume. The resulting mother liquor rapidly precipitated and furnishedan amorphous solid that was collected and dried at 1 mm Hg vacuum toprovide a solid (610 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (app q,J=8.0 Hz, 1H), 7.09 (app d, J=8.3 Hz, 2H), 6.95 (app t, J=7.2 Hz, 1H),6.87 (app t, J=7.4 Hz, 1H), 6.62 (dd, J=17.5, 10.9 Hz, 1H), 6.12 (s,1H), 5.81 (d, J=17.4 Hz, 1H), 5.43 (d, J=10.9 Hz, 1H), 5.25 (br s, 2H),2.07 (s, 3H); LC/MS C-18 column, t_(r)=3.17 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 468 (M+H). ES-HRMS m/z 468.0249 (M+H calcd forC₂₁H₁₅BrF₄NO₂ requires 468.0217).

Example 668

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1,2-dihydroxyethyl)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one

Step 1: Preparation of the title compound. To a room temperaturesolution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(1H)-one(408.0 mg, 0.871 mmol) in water/acetone 1:3 (8.0 mL) was added,sequentially, N-methyl morpholine oxide (268.0 mg, 2.29 mmol) and osmiumtetroxide (4% water solution, 0.25 mL or approximately 10 mg, 0.039mmol). The resulting solution was stirred for 8 hours until completeconsumption of starting material by LCMS analysis, and the reaction wasconcentrated in vacuo to one-fourth original volume. The resultingsolution was diluted with ethyl acetate (300 mL) and washed with water(2×100 mL). The organic extract was separated, Na₂SO₄ dried, andconcentrated in vacuo and the resulting dark residue was subjected toSiO₂ chromatography with ethyl acetate/hexanes/methanol (6:3.5:0.5) tofurnish a solid (389 mg, 88%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.62 (app q,J=8.0 Hz, 1H), 7.26 (dd, J=9.6, 4.5 Hz, 2H), 7 04 (app t, J=8.6 Hz, 2H),6.67 (s, 1H), 5.36 (s, 2H), 4.75 (app t, J=5.6 Hz, 1H), 3.68-3.61 (m,2H), 2.11 (s, 3H); LC/MS C-18 column, t_(r)=2.26 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.) ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0247 (M+H calcd forC₂₁H₁₇BrF₄NO₄ requires 502.0272).

Example 669

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzaldehyde

Step 1: Preparation of the title compound. To a room temperaturesolution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1,2-dihydroxyethyl)-2,6-difluorophenyl]-6-methylpyridin-2(1H)-one(310 mg, 0.615 mmol) in toluene (3.0 mL) was added lead(IV) acetate (443mg, 1.63 mmol). The resulting dark brown solution was stirred for onehour until complete consumption of starting material by LCMS analysis.The reaction mixture was then diluted with ethyl acetate (100 mL), waterwashed (3×100 mL), and brine washed (3×30 mL). The resulting organicextract was separated, Na₂SO₄ dried, and concentrated. The resultingdark residue was subjected to SiO₂ chromatography with ethylacetate/hexanes (1:1) to furnish a light yellow solid (269 mg, 93%).Caution, product is easily air oxidized. ¹H NMR (300 MHz, d₄-MeOH) δ10.05 (s, 1H), 7.68 (app q, J=7.2 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.05(app t, J=8.2 Hz, 2H), 6.73 (s, 1H), 5.40 (s, 2H), 2.15 (s, 3H); LC/MSC-18 column, t_(r)=2.72 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 470(M+H). ES-HRMS m/z 470.0049 (M+H calcd for C₂₀H₁₃BrF₄NO₃ requires470.0009).

Example 670

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzylcarbamate

Step 1: To a room temperature solution of4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzaldehyde(220 mg, 0.468 mmol) in methanol (10 mL) was added solid sodiumborohydride (60.0 mg, 1.58 mmol). The resulting solution evolved gas forapproximately 0.5 minute and was stirred for 10 additional minutes untilcomplete consumption of starting material by LCMS analysis. The reactionwas then diluted with saturated aqueous solution of ammonium chloride(10 mL) and extracted with ethyl acetate (4×50 mL). The organic extractwas separated, Na₂SO₄ dried, and concentrated to a residue. Thisresulting residue was then diluted with methylene chloride (5.0 mL) anda solution of trichloroacetyl isocyanate (toluene, 0.53 M, 1.0 mL, 0.53mmol) was added. The resulting solution was stirred for one hour untilcomplete consumption of starting material by LCMS analysis. The reactionmixture was then directly applied to Al₂O₃ (0.5 g of activity type I)and the slurry was matured for three hours. At this time, the Al₂O₃ plugwas flushed with ethyl acetate/methanol (95:5) and the resulting motherliquor was concentrated to a residue that was subjected to SiO₂chromatography using ethyl acetate/hexanes/methanol (6:3.8:0.2) tofurnish a white solid (181 mg, 75%). ¹H NMR (400 MHz, d₄-MeOH) δ 7.63(app q, J=8.0 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.04 (app t, J=8.1 Hz,2H), 6.68 (s, 1H), 5.37 (s, 2H), 5.12 (m, 2H), 2.11 (s, 3H); LC/MS C-18column, t_(r)=2.54 minutes (5 to 95% acetonitrile/water over 5 minutesat 1 ml/min with detection 254 nm, at 50° C.). ES MS m/z 515 (M+H).ES-HRMS m/z 515.0232 (M+H calcd for C₂₁H₁₆BrF₄N₂O₄ requires 515.0234).

Example 671-687

The following compounds are prepared essentially according to theprocedures outlined in the schemes and the above examples

Example No. Example 671

672

673

674

675

676

677

678

679

680

681

682

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684

685

686

687

688

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700

Example 701

N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-2-hydroxyacetamideStep 1. Preparation of1-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

The compound of Example 606 (10.0 g, 23.38 mmol) was suspended intetrahydrofuran (100 mL) and cooled in an ice-bath. Borane dimethylsulfide (29.9 mL, 2.0 M in tetrahydrofuran, 59.7 mmol) was added. Theresulting mixture was heated to reflux overnight and then cooled in anice-bath. Additional borane dimethyl sulfide (5.85 mL, 2.0 M intetrahydrofuran, 11.7 mmol) was added. The resulting mixture was heatedto reflux overnight and the cooled to room temperature. The flask wasfitted with a distillation head and the reaction was partiallyconcentrated. Additional borane dimethyl sulfide (5.85 mL, 2.0 M intetrahydrofuran, 11.7 mmol) was added. The mixture was heated to refluxovernight and the cooled in an ice-bath. The reaction was quenched bythe addition of 1.0 N HCl (75.0 mL) then partially concentrated. Theaqueous layer was made alkaline with 2.5 N NaOH and a precipitatedeveloped. The solid was collected by filtration washing with diethylether to give a pale purple solid (3.00 g, 32%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.64 (app q, J=7.9 Hz, 1H), 7.44 (d, J=7.9 Hz, 2H), 7.32 (appdt, J=2.4, 9.9 Hz, 1H), 7.14 (app dt, J=1.9, 8.5 Hz, 1H), 7.13 (d, J=7.9Hz, 2H), 6.61 (s, 1H), 5.27 (s, 4H), 3.90 (s, 2H), 2.29 (s, 3H).

Step 2. Preparation ofN-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-2-hydroxyacetamide

Acetoxyacetic acid (1.46 g, 12.35 mmol) was dissolved inN,N-dimethylformamide (30 mL) and 1-Hydroxybenzotriazole (1.84 g, 13.59mmol) was added followed by 4-methylmorpholine (2.04 mL, 18.53 mmol),1-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(compound of step 1) (2.50 g, 6.18 mmol) and then1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.84 g,14.83 mmol). The resulting mixture was stirred at room temperature for 1hour at which time the reaction was diluted with H₂O (100 mL). Thereaction mixture was then extracted with ethyl acetate. The combinedorganic extracts were washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. Chromatography (silica gel,hexanes/ethyl acetate with 10% methanol) provided a white foam. Theresulting foam was dissolved in 10% aqueous methanol (20 mL). K₂CO₃(0.653 g, 4.73 mmol) was added and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated and H₂O(50 mL) was added. The resulting precipitate was collected by filtrationwashing with diethyl ether to give an off-white solid (1.34 g, 47%). ¹HNMR (400 MHz, CDCl₃) δ 7.50 (app q, J=7.7 Hz, 1H), 7.27 (app t, J=5.8Hz, 1H), 7.12 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 6.94-6.89 (m,1H), 6.86-6.81 (m, 1H), 6.09 (s, 2H), 5.23 (s, 2H), 5.18 (s, 2H), 4.53(t, J=5.8 Hz, 1H), 4.33 (d, J=5.9 Hz, 2H), 3.85 (d, J=5.6 Hz, 2H), 2.30(s, 3H). ES-HRMS m/z 463.1256 (M+H calcd for C₂₃H₂₂ClF₂N₂O₄ requires463.1231).

Example 702

N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-1-hydroxycyclopropanecarboxamide

Preparation ofN-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzyl)-1-hydroxycyclopropanecarboxamide.1-Hydroxy-1-cyclopropane-carboxylic acid (1.26 g, 12.35 mmol) wasdissolved in N,N-dimethylformamide (30 mL). 1-Hydroxybenzotriazole (1.84g, 13.59 mmol) was added followed by 4-methylmorpholine (2.04 mL, 18.53mmol),1-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(Example 701, step 1) (2.50 g, 6.18 mmol) and then1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.84 g,14.83 mmol). The resulting mixture was stirred at room temperature for24 hours at which time the reaction was diluted with H₂O (100 mL). Thereaction mixture was then extracted with ethyl acetate. The combinedorganic extracts were washed with saturated NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. Chromatography (silica gel,hexanes/ethyl acetate with 10% methanol) provided a white foam. Theresulting foam was dissolved in 10% aqueous methanol (20 mL) to providean white foam (1.45 g, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.46 (m,1H), 7.34 (t, J=5.9 Hz, 1H), 7.08 (d, J=8.2 Hz, 2H), 6.92 (app d, J=8.2Hz, 2H), 6.92-6.89 (m, 1H), 6.86-6.81 (m, 1H), 6.11 (s, 1H), 5.22 (s,2H), 5.18 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 2.28 (s, 3H), 1.11 (app q,J=4.1 Hz, 2H), 0.90 (app q, J=4.1 Hz, 2H). ES-HRMS m/z 489.1420 (M+Hcalcd for C₂₅H₂₄ClF₂N₂O₄ requires 489.1387).

Example 703

4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate Preparation of4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate

Compound of Example 206 (0.868 g, 1.93 mmol) was suspended indichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M intoluene, 2.12 mmol) was added. The resulting mixture was stirred at roomtemperature for 3 hours then diluted with tetrahydrofuran (50 mL) andAl₂O₃ (5.0 g) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was filtered through a pad of Celite®washing with methanol. The filtrate was then concentrated and theresidue was redissolved in tetrahydrofuran (30 mL). Al₂O₃ (5.0 g) wasadded and the mixture was heated to 40° C. for 3 hours. After cooling toroom temperature, the reaction was filtered through a pad of Celite®washing with methanol. The filtrate was concentrated and the resultingsolid was washed with diethyl ether to give an off-white solid (0.831 g,87%). ¹H NMR (400 MHz, CDCl₃) δ 7.54 (app q, J=7.7 Hz, 1H), 7.25 (d,J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.25 (app dt, J=2.0, 8.3 Hz, 1H),6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s,2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd forC₂₂H₂₀BrF₂N₂O₄ requires 493.0569).

Example 704

2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenyl)amino]-1-methyl-2-oxoethylacetate

To a reaction vessel (borosilicate culture tube) was added compound ofExample 611-(0.300 g, 0.69 mmol) and dichloromethane (3.0 mL). A stocksolution of N-methylmorpholine (0.30 M, 3.0 mL) was added and theparallel reaction apparatus was then orbitally shaken (Labline BenchtopOrbital Shaker) at approximately 200 RPM at room temperature for 10minutes. (S)-(−)-2-Acetoxypropionyl chloride (0.131 mL, 1.04 mmol) wasthen added to the reaction vessel and the reaction apparatus wasorbitally shaken at room temperature for 1.5 hours. At this time thereaction was diluted with dichloromethane (20 mL) and treated withapproximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately3.8 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) andthe orbital shaking was continued at 200 RPM at room temperatureovernight. The reaction vessel was then opened and the solution Phaseproducts were separated from the insoluble quenched byproducts byfiltration and collection into a vial. After partial evaporation theinsoluble byproducts were rinsed with dichloromethane (2×10 mL). Thefiltrate was evaporated by blowing N₂ over the vial to afford anoff-white solid (0.375 g, 99%). ¹H NMR (400 MHz, DMF-d₆) δ 10.14 (s,1H), 7.75 (app dt, J=6.98, 8.59 Hz, 1H), 7.67-7.64 (m, 2H), 7.30 (ddd,J=2.55, 9.26, 11.81 Hz, 1H), 7.21-7.17 (m, 3H), 6.61 (s, 1H), 5.37 (s,4H), 5.11 (q, J=6.85 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 3H), 1.46 (d,J=6.85 Hz, 3H). ES-HRMS m/z 549.0790 (M+H calcd for C₂₅H₂₃BrF₂N₂O₅requires 549.0831).

Example 705

2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenyl)amino]-1,1-dimethyl-2-oxoethylacetate

By the method for Example 704 and substituting(S)-(−)-2-acetoxypropionyl chloride with 2-acetoxy-2-methylpropionylchloride, the title compound was prepared (0.380 g, 98%). ¹H NMR (400MHz, DMF-d₆) δ 9.68 (s, 1H), 7.75 (app dt, J=6.72, 8.60 Hz, 1H),7.71-7.68 (m, 2H), 7.30 (ddd, J=2.55, 9.40, 11.95 Hz, 1H), 7.21-7.15 (m,3H), 6.61 (s, 1H), 5.37 (s, 4H), 2.41 (s, 3H), 2.04 (s, 3H), 1.59 (s,6H). ES-HRMS m/z 563.1027 (M+H calcd for C₂₆H₂₅BrF₂N₂O₅ requires563.0988).

Example 706

{1-[3-(aminocarbonyl)phenyl]-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methylacetate Step 1: Preparation of{1-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl}methylacetate

3-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2 oxopropyl acetate (4.00 g,16.52 mmol) was dissolved in 1,4-dioxane (160 mL) and 3-aminobenzamide(1.73 g, 12.71 mmol) was added. The reaction was heated to reflux for 1hour then cooled to 70° C. Methanesulfonic acid (1.22 g, 12.71 mmol) wasadded and the reaction brought back to reflux for 1 hour. The reactionwas cooled to room temperature, concentrated and used as crude productfor the next step.

Step 2: Preparation of{1-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methylacetate

{1-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl}methylacetate (crude from step 1) (3.61 g, 11.94 mmol) was dissolved inN,N-dimethylformamide (40 mL). K₂CO₃ (3.80 g, 27.46 mmol) was addedfollowed by 2,4-difluorobenzyl bromide (5.44 g, 26.27 mmol). Thereaction mixture was stirred for 48 hours at room temperature. Thereaction mixture was then partially concentrated and the residue takenup in dichloromethane/tetrahydrofuran 1:1 and filtered. The filtrate wascollected, concentrated and the residue tritrated with dichloromethaneto afford a tan solid (1.64 g, 32%). ¹H NMR (400 MHz, DMF-d₆) δ 8.19 (brs, 1H), 8.07 (app dt, J=1.35, 7.66 Hz, 1H), 7.91 (app t, J=1.81 Hz, 1H),7.76 (app dt, J=6.58, 8.59 Hz, 1H) 7.62 (t, J=7.79 Hz, 1H), 7.55 (ddd,J=1.21, 2.01, 7.79 Hz, 1H), 7.46 (br s, 1H), 7.34 (ddd, J=2.55, 9.40,10.47 Hz, 1H), 7.23-7.18 (m, 1H), 6.26 (d, J=2.55 Hz, 1H), 6.11 (d,J=2.69 Hz, 1H), 5.23 (s, 2H), 4.62 (AB q, J_(AB)=14.97 Hz, 2H), 1.96 (s,3H). ES-HRMS m/z 429.1280 (M+H calcd for C₂₂H₁₈F₂N₂O₅ requires429.1257).

Step 3: Preparation of the Title Compound

{1-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methylacetate (from step 2) (1.02 g, 2.39 mmol) was suspended indichloromethane (15 mL) and N-chlorosuccinimide (0.37 g, 2.75 mmol) wasadded. Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and thereaction mixture was stirred at 40° C. for 1.5 hours. The reaction wascooled to room temperature and a precipitate formed. The reactionmixture was diluted with diethyl ether and the precipitate was collectedby filtration and washed with diethyl ether (3×15 mL) to afford a tansolid (0.940 g, 85%). ¹H NMR (400 MHz, DMF-d₆) δ 8.21 (br s, 1H), 8.11(app dt, J=1.48, 7.52 Hz, 1H), 7.95 (app t, J=1.61 Hz, 1H), 7.80 (appdt, J=6.72, 8.59 Hz, 1H) 7.69-7.60 (m, 2H), 7.48 (br s, 1H), 7.35 (ddd,J=2.55, 9.53, 10.61 Hz, 1H), 7.24-7.19 (m, 1H), 6.97 (s, 1H), 5.49 (s,2H), 4.71 (AB q, J_(AB)=15.04 Hz, 2H), 198 (s, 3H). ES-HRMS m/z 463.0883(M+H calcd for C₂₂H₁₇ClF₂N₂O₅ requires 463.0867).

Example 707

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-5-yl]methyl}pyridin-2(1H)-oneStep 1. Preparation of methyl 2-(methylthio)pyrimidine-5-carboxylate

A solution of the sodium salt of3,3-dimethoxy-2-methoxycarbonylpropen-1-ol (5.0 g, 25 mmol),2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in anhydrous methanol(25 mL) was refluxed for 3 hours under anhydrous conditions. Thereaction mixture was cooled and diluted with ethyl acetate. The reactionmixture was filtered and the residue was washed with ethyl acetate. Thefiltrate was concentrated and the residue was purified by flashchromatography (silica gel) using 25% ethyl acetate in hexane to affordthe desired product (3.5 g, 75%) as a white powder. ¹H-NMR (d₆-DMSO, 400MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+HC₇H₈N₂O₂S requires 185.0379).

Step 2. Preparation of [2-(methylthio)pyrimidin-5-yl]methanol

To a cold suspension of methyl 2-(methylthio)pyrimidine-5-carboxylate(1.74 g, 9.4 mmol) in dichloromethane (20 mL, −70° C.) was added DIBAL(20.8 mL, 20 mmol) dropwise via an addition funnel. The mixture wasstirred under nitrogen at −70° C. for 1 hour and then at −50° C. for 3hours. The reaction was diluted with dichloromethane (50 mL) andquenched with a suspension of sodium sulfate decahydrate (10 g) in water(50 mL). The slurry was filtered through celite and the filtrate wasconcentrated. The residue was purified by flash chromatography (silicagel) using 100% ethyl acetate to afford the desired compound (0.7813 g,39%) as a yellow solid. ¹H-NMR ((CD₃OD, 400 MHz) δ 8.53 (s, 2H), 4.56(s, 2H), 2.54 (s, 3H); ES-HRMS m/z 157.0409 (M+H C₆H₈N₂OS requires157.0430).

Step 3. Preparation of 5-(chloromethyl)-2-(methylthio)pyrimidine

To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (0.7813 g,5.0 mmol) in anhydrous dichloromethane (10 mL, 0° C.) was addedtriethylamine (0.836 mL, 8.2 mmol) followed by the addition ofmethanesulfonyl chloride (0.465 mL, 6.0 mmol). The reaction mixturestirred at 0° C. under a nitrogen atmosphere for 30 minutes then at roomtemperature for 3.5 hours. The reaction was quenched with sodiumbicarbonate (5%, 100 mL)) and extracted with dichloromethane (50 mL).The organic extracts were concentrated and the residue was purified byflash chromatography (silica gel) using 15% ethyl acetate in hexane toafford the desired compound (0.720 g, 82%) as a white solid. ¹H-NMR((CD₃OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMSm/z 175.0106 (M+H C₆H₇N₂ClS requires 175.0091).

Step 4. Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-5-yl]methyl}pyridin-2(1H)-one

To a solution of 5-(chloromethyl)-2-(methylthio)pyrimidine (0.62 g, 3.56mmol) in anhdrous DMF (10 mL) was added KBr (0.424, 3.56 mmol). Afterthe suspension stirred at room temperature for 30 minutes,3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.05 g,3.19 mmol) was added followed by NaH (0.102 g, 4.25 mmol). The reactionmixture stirred at 70° C. under a nitrogen atmosphere for 3.5 hours. Thesolvent was distilled and the residue was washed with water andextracted with ethyl acetate. The organic extracts were concentrated andthe residue was purified by reverse phase HPLC using a 10-90%acetonitrile/water (30 minute gradient) at a 70 mL/min flow rate toafford the desired TFA salt (0.32 g, 15%) as a white powder. The TFAcompound was washed with sodium bicarbonate (5%) and extracted withdichloromethane. The organic extract was concentrated to afford thedesired compound (0.295 g, 18%) as a yellow solid. ¹H-NMR (CD₃OD, 400MHz) δ 8.47 (s, 2H), 7.62 (q, 1H, J=8 Hz), 7.03 (m, 2H), 6.51 (s, 1H),5.31 (s, 2H), 5.29 (s, 2H), 2.52 (s, 3H), 2.47 (s, 2H); ES-HRMS m/z468.0174/470.0156 (M+H C₁₉H₁₆N₃O₂F₂BrS requires 468.0187/470.0168).

Example 708

3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-2(1H)-one

To a solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-5-yl]methyl}pyridin-2(1H)-one(example 707) (0.26 g, 0.55 mmol) in acetonitrile:water (4:1 v/v, 10 mL)was added MMPP (0.549 g, 1.1 mmol). The reaction stirred at roomtemperature for 30 hours. The reaction mixture was diluted with ethylacetate and filtered. The filtrate was concentrated and the residue waspurified by reverse phase HPLC using a 10-90% acetonitrile/water (30minute gradient) at a 70 mL/min flow rate to afford the desired TFA saltof the title compound (0.13 g, 38%) as a white powder. ¹H-NMR ((CD₃OD,400 MHz) δ 8.86 (s, 2H), 7.62 (q, 1H, J=8 Hz), 7.02 (m, 2H), 6.56 (s,1H), 5.48 (s, 2H), 5.31 (s, 2H), 3.34 (s, 3H), 2.49 (s, 2H); ES-HRMS m/z500.0109/502.0066 (M+H C₁₉H₁₆N₃O₄F₂BrS requires 500.0086/502.0067).

Example 709

Ethyl2-({[3-bromo-1-(5-{[(2-hydroxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate

To a cooled (−10° C.) solution of3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (0.25 g, 0.46 mmol) and 4-methylmorpholine (0.06 mL, 0.55 mmol) inDMF was added isobutyl chloroformate (0.07 mL, 0.55 mmol). The colorlesssolution gradually turned dark brown. After 30 min, ethaolamine (0.04mL, 0.69 mmol) was added and the solution warmed to RT. After 1 h,solvent was removed and the crude product was purified by preparatoryHPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO₃(20 mL) and extracted in DCM (3×15 mL). The organic extracts were driedover Na₂SO₄, filtered, and concentrated to a white solid, dried in vacuo(0.09 g, 33%). ¹H NMR (CD₃OD/400 MHz) δ 7.88 (m, 1H), 7.61 (s, 1H), 7.53(m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43(s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.68 (t, 2H, J=5.6 Hz), 3.48 (t, 2H,J=5.6 Hz), 2.09 (s, 3H), 2.00 (s, 3H), 1.22 (t, 3H, J=7.2 Hz). ESHRMSm/z 590.1266 and 592.1254 (M+H calculated for C₂₇H₃₀BrFN₃O₆ requires590.1297 and 592.1281).

Example 710

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1H-imidazol-2-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-onetrifluoroacetate

An oven-dried flask was alternately evacuated and flushed with argon.Toluene (2.18 mL) and trimethyl aluminum (1.25 mL, 2.51 mmol) were addedsequentially and the solution cooled to −5° C. Ethylene diamine (0.17mL, 2.51 mmol) was added dropwise. Methyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate(0.75 g, 1.57 mmol) was added portionwise to the cooled solution. Thereaction mixture was then refluxed at 110° C. for 4 h. The solution wascooled and water (0.7 mL), DCM (2.2 mL), and MeOH (2.2 mL) were added.The solution was refluxed for 15 min following this addition and thendried over Na₂SO₄, filtered, and concentrated. The residue was dissolvedin EtOAc (20 mL), refluxed 15 min, dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by preparatory HPLC. Theproduct was isolated by freeze-drying and evaporation of the solvent togive a white solid, dried in vacuo (0.30 g, 31%). ¹H NMR (CD₃OD/400 MHz)δ 7.88 (m, 1H), 7.71 (d, 1H, J=8.0 Hz), 7.64 (m, 2H), 7.05 (m, 2H), 6.70(s, 1H), 5.37 (s, 2H), 4.09 (s, 4H), 2.16 (s, 3H), 2.01 (s, 3H). ESHRMSm/z 488.0750 and 490.0774 (M+H calculated for C₂₃H₂₁BrF₂N₃O₂ requires488.0780 and 490.0762).

Example 711

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(5-hydroxy-1H-pyrazol-3-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-oneStep 1: Preparation of ethyl3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate

In an oven-dried round bottom flask,3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (see Example 487) (0.75 g, 1.62 mmol), DCM (2.00 mL), and oxalylchloride (0.97 mL, 1.94 mmol) were combined under argon. DMF (3-5 drops)was added to aid in dissolution. Stirred at RT overnight. Solvent wasremoved and the crude acid chloride was coevaporated with DCM (3-5 mL×3)and dried in vacuo to give an orange solid. In a separate oven-driedflask, in an argon atmosphere, a solution of monoethyl malonate (0.38mL, 3.23 mmol) in THF (3.00 mL) was cooled to −78° C. Isopropylmagnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solutionwas stirred for 30 min at −78° C. The acid chloride prepared asdescribed above was added dropwise as a solution in THF. The reactionwas warmed to RT. After 30 min, the reaction was cooled (0° C.) and 10%citric acid (5.0 mL) added. The crude product was extracted in EtOAc,washed with 5% NaHCO₃, dried over Na₂SO₄, filtered, and concentrated toa crude brown oil. Recrystallization from DCM and hexane. Filtered abeige solid, dried in vacuo (0.41 g, 47%). ¹H NMR (CD₃OD/400 MHz) δ 8.02(m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J=9.2 Hz), 6.66 (s,1H), 5.36 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H),1.99 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ESHRMS m/z 534.0744 and 536.0746(M+H calculated for C₂₅H₂₃BrF₂NO₅ requires 534.0722 and 536.0706).

Step 2: Preparation of the Title Compound

To a mixture of ethyl3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate(from Step 1) (0.20 g, 0.37 mmol) in EtOH (5.00 mL) was added hydrazinehydrate (0.01 mL, 0.41 mmol). The reaction mixture was heated at 60° C.with a condensere. After 1 h, additional hydrazine hydrate (0.01 mL) wasadded. After 2 h, acetic acid (2 drops) was added. At 4 h, additionalhydrazine was added (0.1 mL). At 5 h, the reaction appeared to becomplete. Left in fridge overnight. Precipitate filtered, washed withhexane, found to be product, a white solid (0.10 g, 54%). ¹H NMR(CD₃OD/400 MHz) δ 7.66 (m, 2H), 7.45 (m, 2H), 7.05 (t, 2H, J=9.6 Hz),6.65 (s, 1H), 5.36 (s, 2H), 2.04 (s, 3H), 2.02 (s, 3H). ESHRMS m/z502.0552 and 504.0569 (M+H calculated for C₂₃H₁₉BrF₂N₃O₃ requires502.0572 and 504.0555).

Example 712

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(5-hydroxyisoxazol-3-yl)-2-methylphenyl]-6-methylpyridin-2(1H)-one

A solution of ethyl3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate(0.20 g, 0.37 mmol), triethylamine (0.06 mL, 0.41 mmol), andhydroxylamine hydrochloride (0.03 g, 0.41 mmol) in EtOH (3.00 mL) washeated overnight at 60° C. with a condenser. Additional triethylamine(0.06 mL) and hydroxylamine hydrochloride (0.03 g) were added. After 2.5h, the additions of triethylamine and hydroxylamine hydrochloride wererepeated. After 1 h, the reaction was concentrated and purified bypreparatory HPLC. The product was isolated by freeze-drying andevaporation of the solvent to give a white solid. Dissolved solid inDCM. Upon addition of 5% NaHCO₃, solution became a milky emulsion. Addedadditional DCM and some brine. Organic extracts were dried over Na₂SO₄,filtered, and concentrated to a pink solid, dried in vacuo (120 mg,64%). ¹H NMR (CD₃OD/400 MHz) δ 7.66 (m, 2H), 7.44 (m, 2H), 7.04 (t, 2H,J=8.8 Hz), 6.64 (s, 1H), 5.36 (s, 2H), 2.04 (s, 3H), 2.01 (s, 3H).ESHRMS m/z 503.0415 and 505.0402 (M+H calculated for C₂₃H₁₈BrF₂N₂O₄requires 503.0413 and 505.0395).

Example 713

3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide

To a cooled (−15° C.) solution of3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoicacid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate(0.10 mL, 0.75 mmol) in DMF (3.00 mL) was added 4-methylmorpholine (0.08mL, 0.75 mmol). The solution instantly turned yellow and was dark brownwithin minutes. After 20 min, methylamine (0.47 mL of 2.0M solution inTHF, 0.94 mmol) was added. The reaction was carried out at RT. After 2.5h, a catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94mmol) were added. After an additional 2.5 h, the reaction wasconcentrated to a dark red oil. The crude product was purified bypreparatory HPLC. Acetonitrile was evaporated and the solution washedwith 5% NaHCO₃ (20 mL) and extracted in DCM (3×15 mL). The organicextracts were dried over Na₂SO₄, filtered, and concentrated to anoff-white solid, dried in vacuo (0.06 g, 19%). ¹H NMR (CD₃OD/400 MHz) δ7.85 (m, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.14 (m, 1H), 7.02 (m, 1H),6.23 (s, 1H), 6.09 (s, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H),2.49 (m, 1H), 2.11 (s, 3H), 1.91 (s, 3H), 0.71 (m, 2H), 0.48 (m, 2H).ESHRMS m/z 493.2260 (M+H calculated for C₂₇H₃₀N₄O₄F requires 493.2246).

Example 714

Methyl4-{[4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-1(2H)-yl]methyl}benzoateStep 1: Preparation of3-bromo-4-[(2,4-difluorobenzyl)oxy]quinolin-2(1H)-one

To a room temperature solution of 4-hydroxy-1,2-dihydroquinolin-2-one(500 mg, 3.10 mmol) in CH₂Cl₂ (10.0 mL) was added portion-wise solid Nbromosuccinimide (551.5 mg, 3.10 mmol). The reaction was stirredvigorously for 1.0 h, followed by the sequential addition of K₂CO₃ (540mg, 3.90 mmol), DMF (4.0 mL), and 2,4-difluorobenzyl bromide (0.430 mL,3.30 mmol). The resulting suspension was stirred for 4.5 hours untilcomplete formation of desired product was seen by LCMS analysis. Thereaction was then diluted with ethyl acetate (400 mL) and brine washed(3×200 mL). The resulting organic extract was Na₂SO₄ dried, filtered,and concentrated in vacuo to a residue that was subjected to SiO₂chromatography with ethyl acetate/hexanes/methanol (60:35:5) to furnisha solid (529 mg, 47%). ¹H NMR (300 MHz, d₆-DMSO) δ 12.23 (s, 1H), 7.68(app q, J=7.5 Hz, 1H), 7.64 (app q, J=8.5 Hz, 1H), 7.54 (app q, J=8.3Hz, 1H), 7.38-7.27 (m, 2H), 7.20 (app t, J=7.4 Hz, 1H), 7.13 (app dt,J=8.4, 2.6 Hz, 1H), 5.25 (s, 2H); LC/MS C-18 column, t_(r)=2.64 minutes(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 366 (M+H). ES-HRMS m/z 365.9967 (M+H calcdfor C₁₆H₁₁BrF₂NO₂ requires 365.9936).

Step 2: Preparation of methyl4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-1(2H)-yl]methyl}benzoate

To a room temperature solution of3-bromo-4-[(2,4-difluorobenzyl)oxy]quinolin-2(1H)-one (400 mg, 1.09mmol) in THF (4.5 mL) was added portion-wise solid sodium hydride (95%oil-free, 60.0 mg, 2.49 mmol). The reaction was vigorously stirred for30 minutes followed by addition of methyl-4-(bromomethyl)-benzoate (400mg, 1.75 mmol). This resulting suspension was then heated to 60° C. for12.0 hours. The resulting solution was then treated with saturatedaqueous ammonium chloride (400 mL) and extracted with ethyl acetate(3×300 mL). The resulting organic extracts were Na₂SO₄ dried, filtered,and concentrated in vacuo to a residue that was subjected to SiO₂chromatography with ethyl acetate/hexanes (60:40) to furnish a solid(396 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (app d, J=8.0 Hz, 2H),7.87 (d, J=7.5 Hz, 1H), 7.60 (app q, J=8.4 Hz, 1H), 7.49 7.42 (m, 1H),7.30-7.15 (m, 4H), 6.94 (app t, J=6.3 Hz, 1H), 6.88 (app t, J=9.4 Hz,1H), 5.64 (s, 2H), 5.33 (s, 2H), 3.88 (s, 3H); LC/MS C-18 column,t_(r)=3.46 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 514 (M+H). ES-HRMSm/z 514.0451 (M+H calcd for C₂₅H₁₉BrF₂NO₄ requires 514.0460).

Step 3: Preparation of the title compound. In a 25 mL round bottom flaskwas added, at room temperature, a solution of methyl4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-1(2H)-yl]methyl}benzoate(step 2) (120 mg, 0.233 mmol) in MeOH (3.0 mL). Next, a combination ofPd on carbon (10% Pd, weight by weight 50% water, 100 mg, 0.047 mmol)and Pd(OAc)₂ (15 mg, 0.067 mmol) was added to the reaction vessel thatpurged with argon and then fitted with a septum. The vessel was thenequipped with a 2.0 L hydrogen balloon (c.a. 20 psi). The resultingsuspension was allowed to stir of 12.0 hours and was then directlyapplied to SiO₂ chromatography using ethyl acetate/hexanes (3:7) tofurnish the desired title compound as a solid (52 mg, 51%). ¹H NMR (300MHz, CDCl₃) δ 8.05-7.98 (m, 3H), 7.55 (app q, J=8.3 Hz, 1H), 7.48 (appt, J=7.5 Hz, 1H), 7.30 (d, J=8.0 Hz 2H), 7.19 (app q, J=8.5, 2H),7.05-6.90 (m, 2H), 6.28 (s, 1II), 5.60 (s, 2H), 5.26 (s, 2H), 3.91 (s,3H); LC/MS C-18 column, t_(r)=3.71 minutes (5 to 95% acetonitrile/waterover 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z436 (M+H). ES-HRMS m/z 436.1371 (M+H calcd for C₂₅H₂₀BrF₂NO₄ requires436.1355).

Example 715

5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furamideStep 1: Preparation of5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoicacid

To a room temperature solution of methyl5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoate(Example 660) (608 g, 1.30 mmol) in THF (8.0 mL) was added dropwise anaqueous solution of sodium hydroxide (3.0 M, 0.50 mL, 1.50 mmol). Thereaction was then heated to 60° C. for 12.0 hours. The resultingsuspension was then diluted with 500 mL of ethyl acetate and neutralizedwith an aqueous solution of hydrochloric acid (1.0 N, 1.5 mL, 10 mmol).The resulting biphasic solution was then concentrated in vacuo to avolume of 50 mL. At this time a white solid began to form and theresulting solid suspension was allowed to sit until precipitationappeared to stop (approximately 1.0 hour). The precipitate was collectedand dried in vacuo (1.0 mm Hg) to furnish the solid acid as anintermediate (500 mg, 85%). ¹H NMR (300 MHz, d₄-MeOH) δ 7.64 (app q,J=8.3 Hz, 1H), 7.18 (d, J=3.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.54 (s, 1H),6.50 (d, J=3.5 Hz, 1H), 5.42 (s, 2H), 5.37 (s, 2H), 2.64 (s, 3H); LC/MSC-18 column, t_(r)=2.38 minutes (5 to 95% acetonitrile/water over 5minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 454(M+H). ES-HRMS m/z 454.0070 (M+H calcd for C₁₉H₁₅BrF₂NO₅ requires454.0096).

Step 2: Preparation of the title compound. To a room temperaturesuspension of5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoicacid (500 mg, 1.10 mmol) in THF (6.0 mL) was added 2-chloro-4,6dimethoxy-1,3,5 triazine (307 mg, 1.75 mmol) and N-methyl morpholine(NMM, 184 mg, 1.82 mmol) sequentially. The resulting solution wasmatured for 2 hours and then a saturated aqueous solution of ammoniumhydroxide (0.70 mL) was added. The resulting suspension was allowed tocontinue for 1 additional hour. The reaction mixture was diluted with400 mL of brine and extracted with ethyl acetate (3×400 mL). The organicextracts were separated, Na₂SO₄ dried, and concentrated in vacuo and theresulting residue was subjected to SiO₂ chromatography with ethylacetate/hexanes/methanol (57:38:5) to provide the title compound (370 g,74%). ¹H NMR (300 MHz, d₄-MeOH) δ 7.64 (app q, J=8.1 Hz, 1H), 7.10-7.00(m, 3H), 6.53 (s, 1H), 6.52 (d, J=3.4 Hz, 1H), 5.43 (s, 2H), 5.32 (s,2H), 2.61 (s, 3H); LC/MS C-18 column, t_(r)=2.15 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 453 (M+H). ES-HRMS m/z 453.0249 (M+H calcd forC₁₉H₁₆BrF₂N₂O₄ requires 453.0256).

Example 716

5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furamideStep 1: Preparation of methyl5-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-furoate

To a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4mmol) in 1,4 dioxane (28.0 mL) was added5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.16g, 44.3 mmol). The reaction was stirred vigorously and heated quickly(within 8 minutes) to an internal temperature of 98° C. Upon reachingtemperature, the reaction was maintained for 1.0 hour. At this time, thereaction was cooled to room temperature rapidly using an ice-bath andmethane sulfonic acid (3.30 g, 34.4 mmol) was added. The reactionmixture was once again brought to an internal temperature ofapproximately 100° C. After 1.0 hour the reaction was diluted with 10 mLof toluene and allowed to cool to room temperature on its own accord. Asolid formed after 3.0 hours that was collected and subsequentlyrecrystallized from methanol/ethyl acetate (1:1). The developingcrystals were allowed to form and stand for 12.0 hours prior tocollection to furnish the desired product as a solid (3.78 g, 44%). ¹HNMR (400 MHz, d₇-DMF) δ 11.34 (s, 1H), 7.43 (app d, J=3.6 Hz, 1H), 6.79(app d, J=3.6 Hz, 1H), 6.01 (s, 1H), 5.63 (d, J=2.0 Hz, 1H), 3.87 (s,3H), 2.02 (s, 3H); LC/MS C-18 column, t_(r)=1.47 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 250 (M+H). ES-HRMS m/z 250.0696 (M+H calcd forC₁₂H₁₂NO₅ requires 250.0710).

Step 2: Preparation of methyl5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate

To a room temperature solution of methyl5-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-furoate (step 1) (3.19 g,12.8 mmol) in DMF (14 mL) was added portion-wise solidN-bromosuccinimide (2.29 g, 12.9 mmol). The reaction was stirredvigorously for 1.0 h, followed by the sequential addition of K₂CO₃ (1.88g, 13.6 mmol), DMF (4.0 mL), and 2,4 difluorobenzyl bromide (2.00 mL,15.55 mmol). The resulting suspension was stirred for 9.0 hours untilcomplete formation of desired product was seen by LCMS analysis. Thereaction was then diluted with saturated brine (300 mL) and extractedwith ethyl acetate (3×300 mL). The resulting organic extracts wereNa₂SO₄ dried, filtered, and concentrated in vacuo to a residue that wassubjected to SiO₂ chromatography with a gradient elution using ethylacetate/hexanes (40:60 to 60:40) to furnish a solid (3.20 mg, 55%). ¹HNMR (400 MHz, d₇-DMF) δ 7.78 (app q, J=8.6 Hz, 1H), 7.48 (app d, J=3.6Hz, 1H), 7.33 (app dt, J=10.0, 2.4 Hz, 1H), 7.21 (app dt, J=8.5, 1.8 Hz,1H), 6.92 (d, J=3.6 Hz, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.88 (s, 3H),2.15 (s, 3H); LC/MS C-18 column, t_(r)=3.11 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0117 (M+H calcd forC₁₉H₁₅BrF₂N₂O₅ requires 454.0096).

Step 3:5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoicacid

To a room temperature solution of methyl5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate(step 2) (3.00 g, 6.61 mmol) in THF (20 mL) was added dropwise anaqueous solution of sodium hydroxide (3.0 M, 4.00 mL, 12.0 mmol). Thereaction was then heated to 60° C. for 12.0 hours. The resultingsuspension was then diluted with 800 mL of ethyl acetate and neutralizedwith an aqueous solution of hydrochloric acid (3.0 N, 4.0 mL, 12 mmol).The resulting biphasic solution was then concentrated in vacuo to avolume of 90 mL. At this time a white solid began to form and theresulting solid suspension was allowed to sit until precipitationappeared to stop (approximately 1.0 hour). The precipitate was collectedand dried in vacuo (1.0 mm Hg) to furnish the solid acid as anintermediate (2.27 g, 78%). ¹H NMR (400 MHz, d₇-DMF) δ 7.79 (app q,J=8.0 Hz, 1H), 7.32 (t, J=9.2 Hz, 1H), 7.20 (app t, J=7.4 Hz, 1H), 6.88(app d, J=2.5 Hz, 1H), 6.74 (s, 1H), 6.51 (d, J=2.5 Hz, 1H), 5.44 (s,2H), 2.10 (s, 3H); LC/MS C-18 column, t_(r)=2.77 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at50° C.). ES-MS m/z 440 (M+H). ES-HRMS m/z 439.9959 (M+H calcd forC₁₈H₁₃BrF₂NO₅ requires 439.9940).

Step 4: Preparation of the Title Compound

To a room temperature suspension of5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoicacid (1.00 g, 2.27 mmol) in THF (8.0 mL) was added 2-chloro-4,6dimethoxy-1,3,5 triazine (610 mg, 3.47 mmol) and N-methyl morpholine(NMM, 368 mg, 3.62 mmol) sequentially. The resulting solution wasmatured for 2 hours and then a saturated aqueous solution of ammoniumhydroxide (1.5 mL) was added. The resulting suspension was allowed tocontinue for 1 additional hour. The reaction mixture was diluted with800 mL of brine and extracted with ethyl acetate (3×600 mL). The organicextracts were separated, Na₂SO₄ dried, and concentrated in vacuo and theresulting residue was subjected to SiO₂ chromatography with ethylacetate/hexanes/methanol (57:38:5) to provide the title compound (710mg, 71%). ¹H NMR (400 MHz, d₇-DMF) δ 8.07 (s, 1H), 7.79 (app q, J=8.6Hz, 1H), 7.50 (br s, 1H), 7.32 (app dt, J=10.1, 2.2 Hz, 1H), 7.30 (appdd, J=8.0, 3.3 Hz, 1H), 7.20 (app dt, J=8.6, 2.0 Hz, 1H), 6.81 (s, 1H),6.79 (d, J=3.4 Hz, 1H), 5.47 (s, 2H), 2.14 (s, 3H); LC/MS C-18 column,t_(r)=2.60 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min with detection 254 nm, at 50° C.). ES-MS m/z 439 (M+H). ES-HRMSm/z 439.0088 (M+H calcd for C₁₈H₁₄BrF₂N₂O₄ requires 439.0010).

Example 717

1-[3,5-bis(hydroxymethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-oneStep 1: Preparation of dimethyl5-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)isophthalate

Dimethyl 5-aminoisophthalate (24.45 g, 117 mmol) was dissolved in 500 mltoluene and heated to reflux.5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (40.0g, 175.3 mmol) was added and refluxed for 15 minutes. The reaction wasevaporated. 500 ml of acetonitrile and p-toluenesulphonic acid (22.25 g,117 mmol) was added and refluxed for 1 hour. The reaction was allowed tocool to room temperature and stand over night. The resulting precipitatewas filtered, washed three times with 250 ml water and 250 mlacetonitrile and dried in vacuo to give a tan solid (18.85 g, 51%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (br s, 1H), 8.47 (t, J=1.54Hz, 1H), 7.99 (d, J=1.47 Hz, 2H), 5.90 (d, J=1.61 Hz, 1H), 5.55 (d,J=2.42 Hz, 1H), 3.87 (s, 6H), 1.82 (s, 3H); LC/MS, t_(r)=1.79 minutes (5to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 318 (M+H). ES-HRMS m/z 318.0994 (M+H calcd for C₁₆H₁₆NO₆requires 318.0972).

Step 2: Preparation of dimethyl5-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)isophthalate

Dimethyl 5-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)isophthalate (fromStep 1) (18.0 g, 56.7 mmol) was stirred at room temperature withN-Bromosuccinimide (10.6 g, 59.6 mmol) in 35 ml of N,N-dimethylformamideand 180 ml of methylene chloride. After stirring for 1 hour, a whiteprecipitate had formed. The precipitate was filtered, washed withacetonitrile and dried in vacuo to give a white solid (11.55 g, 51%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.49 (br s, 1H), 8.49 (t, J=1.24 Hz, 1H), 8.06(d, J=1.47 Hz, 2H), 6.07 (s, 1H), 3.88 (s, 6H), 1.82 (s, 3H); LC/MS,t_(r)=1.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min, at 254 nm, at 50° C.), ES-MS m/z 396 (M+H). ES-HRMS m/z 396.0102(M+H calcd for C₁₆H₁₅BrNO₆ requires 396.0077).

Step 3: Preparation of dimethyl5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalate

Dimethyl5-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)isophthalate (fromStep 2) (11.3 g, 28.5 mmol) was stirred briskly with2,4-difluorobenzylbromide (3.66 ml, 28.5 mmol) and K₂CO₃ (5.91 g, 42.8mmol) in 50 ml of N,N-dimethylformamide at room temperature for 3 hours.The reaction was then poured into 1 L of cold water and the resultingprecipitate was filtered, washed with water and diethyl ether, and driedin vacuo to yield a white solid (13.8 g, 93%). ¹H NMR (400 MHz, DMSO-d₆)δ 8.51 (t, J=1.60 Hz, 1H), 8.12, (d, J=1.60 Hz, 2H), 7.67 (app q, J=7.92Hz, 1H), 7.34 (app dt, J=9.94, 2.19 Hz, 1H), 7.17 (dt, J=8.53, 2.11 Hz,1H), 6.68 (s, 1H), 5.33 (s, 2H), 3.88 (s, 6H), 1.93 (s, 3H); LC/MS,t_(r)=2.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min, at 254 nm, at 50° C.), ES-MS m/z 522 (M+H). ES-HR/MS m/z522.0335 (M+H calcd for C₂₃H₁₉BrF₂NO₆ requires 522.0358).

Step 4; Preparation of5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalicacid

Dimethyl5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalate(from Step 3) (5.0 g, 9.57 mmol) was stirred at room temperature with2.5 N NaOH (15.3 ml, 38.3 mmol) in 30 ml of 5:1 THF/water for 1 hour.The reaction was then acidified with 1 N HCl and the resultingprecipitate was filtered, washed with water, and dried in vacuo to yielda white solid (4.48 g, 95%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (br s,2H), 8.51 (t, J=1.41 Hz, 1H), 8.02, (d, J=1.48 Hz, 2H), 7.67 (app q,J=7.88 Hz, 1H), 7.32 (dt, J=9.94, 2.19 Hz, 1H), 7.16 (dt, J=8.52, 1.99Hz, 1H), 6.68 (s, 1H), 5.32 (s, 2H), 1.94 (s, 3H); LC/MS, t_(r)=2.27minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254nm, at 50° C.), ES-MS m/z 494 (M+H). ES-HRMS m/z 494.0054 (M+H calcd forC₂₁H₁₅BrF₂NO₆ requires 494.0045).

Step 5: Preparation of the title compound.5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalicacid (from Step 4 above) (500 mg, 1.01 mmol) was added to a solution of1M borane-dimethylsulfide complex in tetrahydrofuran (9.0 ml, 9.00 mmol)in 2.5 ml tetrahydrofuran at 0° C. The reaction was allowed to warm toroom temperature while stirring. After stirring overnight, more 1Mborane-dimethylsulfide complex in tetrahydrofuran (0.60 ml, 0.60 mmol)was added and stirring at room temperature. After 4 hours, ice chipswere added to quench the reaction. The reaction was extracted 2 timeswith ethyl acetate and the combined organic layers were washed withbrine, dried over MgSO₄ and evaporated. The resulting solid was washedwith acetonitrile and diethyl ether and dried in vacuo to give a whitesolid (281 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (app q, J=7.92 Hz,1H), 7.35 (s, 1H), 7.33 (dt, J=9.40, 2.24 Hz, 1H), 7.16 (dt, J=8.52,1.88 Hz, 1H), 6.99 (s, 2H), 6.62 (s, 1H), 5.31 (s, 2H), 5.27 (br s, 2H),4.51 (s, 4H), 1.93 (s, 3H); LC/MS, t_(r)=2.19 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 466 (M+H). ES-HRMS m/z 466.0454 (M+H calcd for C₂₁H₁₉BrF₂NO₄requires 466.0460).

Example 718

5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalamide

5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalicacid (Example 717, step 4) (500 mg, 1.01 mmol) was dissolved in 4 ml oftetrahydrofuran. 0.5M ammonia in 1,4-dioxane (12.12 ml, 6.06 mmol) wasadded, followed, in order, by EDCI (494 mg, 2.53 mmol),1-hydroxybenzotriazole (342 mg, 2.53 mmol) and triethylamine (563 μl,4.04 mmol). The reaction was stirred at room temperature overnight. Thereaction evaporated and water was used to triturate the product. Theresulting solid was filtered and washed with water, acetonitrile, ethylacetate and diethyl ether, and dried in vacuo to give a white solid (202mg, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.08 (br s, 2H),7.86, (d, J=1.34 Hz, 2H), 7.67 (app q, J=7.92 Hz, 1H), 7.55 (br s, 2H),7.33 (dt, J=9.94, 2.18 Hz, 1H), 7.17 (dt, J=8.59, 1.92 Hz, 1H), 6.70 (s,1H), 5.34 (s, 2H), 1.96 (s, 3H); LC/MS, t_(r)=2.10 minutes (5 to 95%acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.),ES-MS m/z 492 (M+H). ES-HRMS m/z 492.0381 (M+H calcd for C₂₁H₁₇BrF₂N₃O₄requires 492.0365).

Example 719

1-[3,5-bis(1-hydroxy-1-methylethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one

Dimethyl5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]isophthalate(Example 717, step 3) (500 mg, 0.96 mmol) was added dropwise to asolution of 3M MeMgBr in diethyl ether (1.6 ml, 4.79 mmol) in 15 ml oftetrahydrofuran at −5° C. and stirred at 5% C. The reaction turned red.After 2.5 hours, the reaction was quenched with a saturated NH₄Clsolution and extracted 2 times with ethyl acetate. The combined organiclayers were washed with NaHCO₃ solution and brine, dried over MgSO₄ andevaporated. The resulting solid was washed with diethyl ether and driedin vacuo to give a white solid (329 mg, 66%). ¹H NMR (400 MHz, DMSO-d₆)δ 7.69-7.63 (m, 2H), 7.33 (dt, J=9.87, 2.41 Hz, 1H), 7.16 (dt, J=8.46,1.75 Hz, 1H), 7.07 (d, J=1.48 Hz, 2H), 6.61 (s, 1H), 5.32 (s, 2H), 5.06(s, 2H), 1.89 (s, 3H), 1.41 (s, 12H); LC/MS, t_(r)=2.45 minutes (5 to95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C.), ES-MS m/z 522 (M+H). ES-HRMS m/z 522.1098 (M+H calcd forC₂₅H₂₇BrF₂NO₄ requires 522.1086).

Example 720

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoicacid (Example 203) (500 mg, 1.11 mmol) was added to a solution of 2Mborane-dimethylsulfide complex in tetrahydrofuran (3.33 ml, 6.66 mmol)in 2.5 ml tetrahydrofuran at 0° C. The reaction was allowed to warm toroom temperature while stirring. After 2.5 hours, ice chips were addedto quench the reaction. The resulting precipitate was filtered, washedwith diethyl ether and dried in vacuo to give a white solid (160 mg,33%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (app q, J=7.88 Hz, 1H), 7.42 (d,J=8.19 Hz, 2H), 7.33 (dt, J=9.87, 2.06 Hz, 1H), 7.19-7.14 (m, 3H), 6.62(s, 1H), 5.31 (s, 2H), 5.30 (s, 1H), 4.54 (d, J=5.24, 2H), 1.92 (s, 3H);LC/MS, t_(r)=2.36 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 436 (M+H). ES-HRMS m/z436.0374 (M+H calcd for C₂₀H₁₇BrF₂NO₃ requires 436.0354).

Example 721

3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-methylpyridin-2(1H)-one

Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate(Example 202) (500 mg, 1.08 mmol) was added dropwise to a solution of 3MMeMgBr in diethyl ether (0.90 ml, 2.69 mmol) in 15 ml of tetrahydrofuranat −5° C. and stirred at −5° C. After 2.75 hours, more 3M MeMgBr indiethyl ether (0.45 ml, 1.35 mmol) was added and stirred at −5° C. After4 hours, the reaction was quenched with a saturated NH₄Cl solution andextracted 2 times with ethyl acetate. The combined organic layers werewashed with NaHCO₃ solution and brine, dried over MgSO₄ and evaporated.The resulting solid was washed with diethyl ether and dried in vacuo togive a white solid (268 mg, 53%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (appq, J=7.92 Hz, 1H), 7.57 (d, J=8.46 Hz, 2H), 7.33 (dt, J=9.87, 2.11 Hz,1H), 7.16 (dt, J=8.59, 2.24 Hz, 1H), 7.14 (d, J=8.63 Hz, 2H), 6.62 (s,1H), 5.31 (s, 2H), 5.12 (s, 1H), 1.91 (s, 3H), 1.44 (s, 6H); LC/MS,t_(r)=2.54 minutes (5 to 95% acetonitrile/water over 5 minutes at 1ml/min, at 254 nm, at 50° C.), ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0604(M+H calcd for C₂₂H₂₁BrF₂NO₃ requires 464.0667).

Example 722

1-(5-amino-2-fluorophenyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride Step 1 Preparation of tert-butyl3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenylcarbamate

A solution of the compound of Example 519 (4.3 g, 9.2 mmol) intert-butanol (50 mL) was flushed with nitrogen. Diphenyl phosphorylazide (2 mL, 9.2 mmol) and triethyl amine (1.3 mL, 9.2 mmol) were added.After heating at 90 C for 20 h, the reaction mixture was concentrated invacuo. The residue was diluted with methylene chloride and was washedsequentially with aqueous ammonium chloride and aqueous NaHCO₃. Theorganic layer was concentrated in vacuo; the resulting solids weresuspended in acetonitrile and filtered to give the title compound (2.9g, 58%). ¹H NMR (400 MHz, CD₃OD) δ 7.64 (q, J=7.2 and 14.4 Hz, 1H), 7.49(m, 1H), 7.43 (m, 1H), 7.24 (t, J=9.6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H),6.62 (s, 1H), 5.35 (s, 2H), 2.09 (s, 3H), 1.49 (s, 9H) ppm. ¹⁹F NMR (300MHz, CD₃OD) δ −111.53 (1F), −115.93 (1F), −132.58 ppm. ES-HRMS m/z540.0822 (M+H calcd for C₂₄H₂₃BrF₃N₂O₄ requires 540.0820).

Step 2 Preparation of1-(5-amino-2-fluorophenyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-onehydrochloride

The product of Step 1, (2.9 g, 5.3 mmol) was dissolved intetrahydrofuran (75 mL) and 6N HCl (10 mL). The reaction mixture washeated at 60 C for 18 h and was concentrated in vacuo to give the finalproduct (1.89 g, 75%). ¹H NMR (400 MHz, CD₃OD) δ 7.64 (q, J=8.4 and 15.2Hz, 1H), 7.56 (m, 2H), 7.46 (m, 1H), 7.05 (m, 2H), 6.69 (s, 1H), 5.37(s, 2H), 2.10 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.37 (1F),−115.86 (1F), −123.16 ppm. ES-HRMS m/z 440.0334 (M+H calcd forC₁₉H₁₅BrF₃N₂O₂ requires 440.0295).

Example 723

N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxyacetamideStep 1 Preparation of2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}amino)-2-oxoethylacetate

A solution of the compound of Example 722 (0.5 g, 1.05 mmol) intetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring atroom temperature for 2 h, the reaction was complete. The reactionmixture was poured into saturated aqueous ammonium chloride. The solidswere filtered off and were washed with water and diethyl ether. Titleproduct was isolated as a white solid (0.32 g, 58%). ¹H NMR (400 MHz,CD₃OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H),6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H)ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ −111.56 (1F), −115.99 (1F), −129.48 (1F)ppm. LC/MS, t_(r)=5.35 minutes (5 to 95% acetonitrile/water over 8minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540(M+H).

Step 2 Preparation ofN-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxyacetamide

The product of Step 1, (0.1 g, 0.18 mmol) was suspended intetrahydrofuran (10 mL), methanol (2 mL), and 2.5 N NaOH (1 mL). Afterstirring at room temperature for 1 hour, the reaction was complete andthe organics were removed in vacuo. The aqueous layer was acidified topH 1 with 6N HCl, the solids were suspended in water, filtered, andwashed with diethyl ether. The title compound was obtained as a whitepowder (56.2 mg, 61%). ¹H NMR (400 MHz, CD₃OD) δ 7.75 (dq, J=2.9, 4.8and 9.2 Hz, 1H), 7.71 (dd, J=2.4 and 6.8 Hz, 1H), 7.64 (q, J=8 and 14.8Hz, 1H), 7.32 (t, J=9.6 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 6.64 (s, 1H),5.36 (s, 2H), 4.10 (s, 2H), 2.10 (s, 3H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ−111.54 (1F), −115.99 (1F), −129.71 (1F) ppm. LC/MS, t_(r)=5.04 minutes(5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 498 (M+H).

Example 724

N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxy-2-methylpropanamideStep 1 Preparation of2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}amino)-1,1-dimethyl-2-oxoethylacetate

A solution of the compound of Example 722 (0.5 g, 1.05 mmol) intetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1mmol) and 1-chlorocarbonyl-1-methylethyl acetate (0.16 mL, 1.15 mmol).After stirring at room temperature for 2 h, the reaction was complete.The reaction mixture was poured into saturated aqueous ammoniumchloride. The solids were filtered off and were washed with water anddiethyl ether. The compound of Step 1 was isolated as a white solid(0.23 g, 39%). ¹H NMR (400 MHz, CD₃OD) δ 7.64 (m, 2H), 7.54 (dd, J=2.8and 6.8 Hz, 1H), 7.30 (t, J=9.2 Hz, 1H), 7.04 (t, J=9.2 Hz, 2H), 6.64(s, 1H), 5.35 (s, 2H), 2.11 (s, 3H), 2.08 (s, 3H), 1.61 (s, 6H) ppm. ¹⁹FNMR (400 MHz, CD₃OD) δ −111.57 (1F), −116.00 (1F), −129.56 (1F) ppm.LC/MS, t_(r)=5.65 minutes (5 to 95% acetonitrile/water over 8 minutes at1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 568 (M+H).

Step 2 Preparation ofN-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxy-2-methylpropanamide

The product of Step 1-(0.1 g, 0.17 mmol) was suspended intetrahydrofuran (10 mL), methanol (2 mL), and 2.5 N NaOH (1 mL). Afterstirring at room temperature for 1 hour, the reaction was complete andthe organics were removed in vacuo. The aqueous layer was acidified topH 1 with 6N HCl, the solids were suspended in water, filtered, andwashed with diethyl ether. The title compound was obtained as a whitepowder (56 mg, 61%). ¹H NMR (400 MHz, CD₃OD) δ 7.75 (dq, J=2.8, 4.4 and9.2 Hz, 1H), 7.69 (dd, J=2.8 and 6.8 Hz, 1H), 7.64 (q, J=8 and 14.8 Hz,1H), 7.31 (t, J=9.2 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35(s, 2H), 2.10 (s, 3H), 1.43 (s, 6H) ppm. ¹⁹F NMR (400 MHz, CD₃OD) δ−111.55 (1F), −115.95 (1F), −129.80 (1F) ppm. LC/MS, t_(r)=5.34 minutes(5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection254 nm, at 50° C.). ES-MS m/z 526 (M+H).

Example 725

4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluoro-N,N-dimethylbenzamideStep 1 Preparation of4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluorobenzoicacid

Compound of Example 604 (4.1 g, 8.5 mmol) was suspended intetrahydrofuran (30 mL), methanol (15 mL), water (15 mL) and 2.5 N NaOH(6.8 mL, 17 mmol)). After stirring at room temperature for 2 hour, thereaction was complete and the organics were removed. The aqueous layerwas acidified to pH 1 with 3N HCl, the solids were suspended in water,filtered, and washed with diethyl ether. The title compound was obtainedas a white powder and used without further purification (4.4 g). ¹H NMR(400 MHz, CD₃OD) δ 8.00 (dd, J=1.8 and 8.8 Hz, 1H), 7.93 (dd, J=1.48 and10 Hz, 1H), 7.64 (q, J=8 and 14.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.05(t, J=10 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 2.08 (s, 3H) ppm. ¹⁹F NMR(400 MHz, CD₃OD) δ −111.48 (1F), −115.96 (1F), −123.35 (1F) ppm. ES-HRMSm/z 468.9987 (M+H calcd for C₂₀H₁₄BrF₃NO₄ requires 469.0086).

Step 2 Preparation of4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-fluoro-N,N-dimethylbenzamide

A solution of the product of Step 1-(0.5 g, 1.07 mmol) in N,N-dimethylformamide was cooled to 0 C. Iso-butyl chloroformate (0.14 mL, 1.07mmol) and N-methyl morpholine (0.12 mL, 1.07 mmol) were added. After 20minutes, N,N-dimethylamine (2.0 M, 1.1 mL, 2.14 mmol) was added and thereaction mixture was warmed to room temperature over 18 h. The reactionmixture was partitioned between ethyl acetate and saturated aqueousNaHCO₃. The organics were washed with brine and concentrated in vacuo.The resulting semi-solid was treated with ethyl acetate and acetone toprecipitate the title compound (90 mg, 17%). ¹H NMR (400 MHz, dmso-d₆) δ7.67 (q, J=8 and 14.8 Hz, 1H), 7.52 (m, 2H), 7.35 (m, 2H), 7.18 (td,J=2.8 and 8.8 Hz, 1H), 6.73 (s, 1H), 5.34 (s, 2H), 2.98 (s, 3H), 2.91(s, 3H), 2.00 (s, 3H) ppm. ¹⁹F NMR (400 MHz, dmso-d₆) δ −109.50 (1F),−113.63 (1F), −122.09 (1F) ppm. ES-HRMS m/z 496.0570 (M+H calcd forC₂₂H₁₉BrF₃N₂O₃ requires 496.0558).

Example 726

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)methyl]-6-methylpyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 633 (180 mg, 0.43 mmol),acetoxyacetyl chloride (51 μL, 0.47 mmol), triethylamine (119 μL, 0.86mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 minthe reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) andMeOH (2.0 mL) was added and stirred for 20 min to give the titlecompound. The compound precipitated out of solution. The precipitatedwas filtered and washed with water and diethyl ether to obtain the titlecompound (130 mg, 64%) as a white solid. ¹H NMR (400 MHz, (DMSO) δ 7.9(d, J=8.2, 1H), 7.6 (q, J=8.5 and 6.9 Hz, 1H), 7.3 (t, J=8.7 Hz, 1H),7.1 (t, J=7.9 Hz, 1H), 6.9 (s, 2H), 6.5 (s, 1H), 5.25 (s, 2H), 4.1 (d,J=5.5 Hz, 2H), 3.9 (t, J=8.6 Hz, 2H), 3.42 (t, J=5.4 Hz, 1H), 3.35 (t,J=4.8 Hz, 1H), 3.2 (t, J=8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z475.1220 (M+H calcd for C₂₄H₂₂ClF₂N₂O₄ requires 475.1231).

Example 727

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-indol-5-yl]methyl}-6-methylpyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 633 (200 mg, 0.48 mmol),1-chlorocarbonyl-1-methylethyl acetate (104.3 μL, 0.72 mmol),triethylamine (133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). Afterstirring at 25° C. for 20 min the reaction was completed by LC-MS. NaOH(2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20min to give the title compound. The compound precipitated out ofsolution. The precipitate was filtered and washed with water and diethylether to obtain a white solid (240 mg, 99%). ¹H NMR (400 MHz, (DMSO) δ8.0 (d, J=8.3, 1H), 7.6 (q, J=8.6 and 6.9 Hz, 1H), 7.3 (td, J=2.5 and7.8 Hz, 1H), 7.1 (td, J=1.75 and 6.7 Hz, 1H), 6.95 (s, 1H), 6.89 (d,J=8.5 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.3 (t, J=8.3 Hz, 2H), 3.42(t, J=5.4 Hz, 1H), 3.35 (t, J=5.2 Hz, 1H), 3.0 (t, J=8.2 Hz, 2H), 2.3(s, 3H), 1.3 (s, 6H) ppm. ES-HRMS m/z 503.1561 (M+H calcd forC₂₆H₂₆ClF₂N₂O₄ requires 503.1544).

Example 728

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(methoxyacetyl)-2,3-dihydro-1H-indol-5-yl]methyl}-6-methylpyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 633 (200 mg, 0.48 mmol),methoxyacetyl chloride (66 μL, 0.72 mmol), triethylamine (134 μL, 0.96mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 minthe reaction was completed by LC-MS. The compound precipitated out ofsolution. The precipitate was filtered and washed with water and diethylether to obtain a white solid (195 mg, 83%). ¹H NMR (400 MHz, (DMSO) δ8.0 (d, J=8.0, 1H), 7.6 (q, J=8.6 and 6.7 Hz, 1H), 7.3 (td, J=2.4 and6.7 Hz, 1H), 7.1 (td, J=1.88 and 6.6 Hz, 1H), 6.9 (s, 2H), 6.58 (s, 1H),5.25 (s, 2H), 4.15 (s, 2H), 3.9 (t, J=8.3 Hz, 2H), 3.45 (m, 1H), 3.4 (m,1H), 3.32 (s, 3H), 3.0 (t, J=8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z489.1387 (M+H calcd for C₂₅H₂₄ClF₂N₂O₄ requires 489.1387).

Example 729

5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylindoline-1-carboxamide

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 633 (200 mg, 0.48 mmol),dimethylcarbamyl chloride (66 μL, 0.72 mmol), triethylamine (133 μL,0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at 250° C. for 5min the reaction was completed by LC-MS. The compound precipitated outof solution. The precipitate was filtered and washed with water anddiethyl ether to obtain a white solid (198 mg, 85%). ¹H NMR (400 MHz,(DMSO) δ 7.6 (q, J=7.4 Hz, 1H), 7.3 (t, J=8.9 Hz, 1H), 7.1 (t, J=8.5 Hz,2H), 6.93 (s, 1H), 6.86 (s, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 3.9 (t,J=8.2 Hz, 2H), 3.45 (m, 1H), 3.4 (m, 1H), 2.9 (t, J=8.3 Hz, 2H), 2.8 (s,6H), 2.3 (s, 3H) ppm. ES-HRMS m/z 488.1548 (M+H calcd for C₂₅H₂₄ClF₂N₂O₄requires 488.1547).

Example 730

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)methyl]pyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 88 (200 mg, 0.5 mmol),acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0mmol) and tetrahydrofuran (3.0 mL). After stirring at 25° C. for 20 minthe reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) andMeOH (2.0 mL) was added and stirred for 20 min to give the titlecompound. The compound precipitated out of solution. The precipitatedwas filtered and washed with water and diethyl ether to obtain the titlecompound (200 mg, 83%) as a white solid. ¹H NMR (400 MHz, (DMSO) δ 7.98(d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H),7.3 (dt, J=2.4 and 7.2 Hz, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H),5.25 (s, 2H), 5.1 (s, 2H), 4.8 (t, J=5.8 Hz, 1H), 4.1 (d, J=5.6 Hz, 2H),3.9 (t, J=7.9 Hz, 2H), 3.1 (t, J=7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088(M+H calcd for C₂₃H₂₀ClF₂N₂O₄ requires 461.1074).

Example 731

Preparation of3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(1-glycoloyl-2,3-dihydro-1H-indol-5-yl)methyl]pyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with compound of Example 88 (200 mg, 0.50 mmol),1-chlorocarbonyl-1-methylethyl acetate (80 μL, 0.55 mmol), triethylamine(140 μL, 1.0 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25°C. for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24mmol, 1.5 mL) and MeOH (2.0 mL) was added and stirred for 20 min to givethe title compound. The compound precipitated out of solution. Theprecipitated was filtered and washed with water and diethyl ether toobtain the title compound (136 mg, 55%) a white solid. ¹H NMR (400 MHz,(DMSO) δ 7.98 (d, J=8.1, 1H), 7.9 (d, J=7.8 Hz, 1H), 7.6 (q, J=8.6 and6.6 Hz, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s,2H), 5.0 (s, 2H), 4.3 (t, J=7.8 Hz, 2H), 3.0 (t, J=7.9 Hz, 2H), 1.3 (s,6H) ppm. ES-HRMS m/z 489.1376 (M+H calcd for C₂₅H₂₄ClF₂N₂O₄ requires489.1387).

Example 732

3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(methoxyacetyl)-2,3-dihydro-1H-indol-5-yl]methyl}pyridin-2(1H)-one

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the compound of Example 88 (200 mg, 0.5 mmol),methoxyacetyl chloride (69 μL, 0.75 mmol), triethylamine (139 μL, 1.0mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 20 minthe reaction was completed by LC-MS. The compound precipitated out ofsolution. The precipitate was filtered and washed with water and diethylether to obtain a white solid (195 mg, 83%). ¹H NMR (400 MHz, (DMSO) δ7.98 (d, J=8.2, 1H), 7.9 (d, J=7.7 Hz, 1H), 7.6 (d, J=8.5 Hz, 1H), 7.3(t, J=9.6 Hz, 1H), 7.1 (m, 3H), 6.56 (d, J=7.8 Hz, 1H), 5.25 (s, 2H),5.l (s, 2H), 4.1 (s, 2H), 3.98 (t, J=7.9 Hz, 2H), 3.33 (s, 3H), 3.0 (t,J=7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088 (M+H calcd for C₂₃H₂₀ClF₂N₂O₄requires 461.1074).

Example 733

5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]2-oxopyridin-1(2H)-yl]methyl}-N,N-dimethylindoline-1-carboxamide

A 10 mL round bottomed flask equipped with stirbar and nitrogen inletwas charged with the compound of Example 88 (200 mg, 0.5 mmol),dimethylcarbamyl chloride (69 μL, 0.75 mmol), triethylamine (139 μL, 1.0mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 5 minthe reaction was completed by LC-MS. The compound precipitated out ofsolution. The precipitate was filtered and washed with water and diethylether to obtain a white solid (188 mg, 58%). ¹H NMR (400 MHz, (DMSO) δ7.9 (d, J=8.1, 1H), 7.6 (q, J=8.6 and 6.6 Hz, 1H), 7.3 (t, J=9.3 Hz,1H), 7.1 (m, 3H), 6.8 (d, J=8.0 Hz, 1H), 6.5 (d, J=7.8 Hz, H), 5.25 (s,2H), 5.0 (s, 2H), 3.7 (t, J=8.6 Hz, 2H), 2.9 (t, J=7.9 Hz, 2H), 2.8 (s,6H) ppm. ES-HRMS m/z 474.1387 (M+H calcd for C₂₄H₂₃ClF₂N₃O₃ requires474.1391).

Biological Evaluation

p38 Kinase Assay

Cloning of Human p38a:

The coding region of the human p38a cDNA was obtained byPCR-amplification from RNA isolated from the human monocyte cell lineTHP.1. First strand CDNA was synthesized from total RNA as follows: 2 μgof RNA was annealed to 100 ng of random hexamer primers in a 10 μlreaction by heating to 70° C. for 10 minutes followed by 2 minutes onice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega,Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5× buffer, 2 μl of 100 mMDTT and 1 μl (200 U) of Superscript II™ reverse transcriptase. Randomprimer, dNTP's and Superscript II™ reagents were all purchased fromLife-Technologies, Gaithersburg, Mass. The reaction was incubated at 42°C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5μl of the reverse transcriptase reaction into a 100 μl PCR reactioncontaining the following: 80 μl dH.sub.2 O, 2. μl mM dNTP's, 1 μl eachof forward and reverse primers (50 pmol/μl), 10 μl of 10× buffer and 1μl Expand™ polymerase (Boehringer Mannheim). The PCR primersincorporated Bam HI sites onto the 5′ and 3′ end of the amplifiedfragment, and were purchased from Genosys. The sequences of the forwardand reverse primers were 5′-GATCGAGCATTCATGTCTCAGGAGAGGCCCA-3′ and5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplificationwas carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2minutes. After amplification, excess primers and unincorporated dNTP'swere removed from the amplified fragment with a Wizard™ PCR prep(Promega) and digested with Bam HI (New England Biolabs). The Bam HIdigested fragment was ligated into BamHI digested pGEX 2T plasmid DNA(PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) asdescribed by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nded. (1989). The ligation reaction was transformed into chemicallycompetent E. coli DH10B cells purchased from Life-Technologies followingthe manufacturer's instructions. Plasmid DNA was isolated from theresulting bacterial colonies using a Promega Wizard™ miniprep kit.Plasmids containing the appropriate Bam HI fragment were sequenced in aDNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.).cDNA clones were identified that coded for both human p38a isoforms (Leeet al. Nature 372, 739). One of the clones that contained the cDNA forp38a-2 (CSB-2) inserted in the cloning site of PGEX 2T, 3′ of the GSTcoding region was designated pMON 35802. The sequence obtained for thisclone is an exact match of the cDNA clone reported by Lee et al. Thisexpression plasmid allows for the production of a GST-p38a fusionprotein.

Expression of Human p38a

GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E.coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultureswere grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The nextday, 500 ml of fresh LB was inoculated with 10 ml of overnight culture,and grown in a 2 liter flask at 37° C. with constant shaking until theculture reached an absorbance of 0.8 at 600 nm. Expression of the fusionprotein was induced by addition of isopropyl b-D-thiogalactosidase(IPTG) to a final concentration of 0.05 mM. The cultures were shaken forthree hours at room temperature, and the cells were harvested bycentrifugation. The cell pellets were stored frozen until proteinpurification.

Purification of P38 Kinase-Alpha

All chemicals were from Sigma Chemical Co. unless noted. Twenty grams ofE. coli cell pellet collected from five 1 L shake flask fermentationswas resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mMNa.sub.2 HPO.sub.4, 1.8 mM KH.sub.2 PO.sub.4, pH 7.3) up to 200 ml. Thecell suspension was adjusted to 5 mM DTT with 2 M DTT and then splitequally into five 50 ml Falcon conical tubes. The cells were sonnicated(Ultrasonics model W375) with a 1 cm probe for 3.times.1 minutes(pulsed) on ice. Lysed cell material was removed by centrifugation(12,000×g, 15 minutes) and the clarified supernatant applied toglutathione-sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography

Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200ml clarified supernatant and incubated batchwise for 30 minutes at roomtemperature. The resin was collected by centrifugation (600.times.g, 5min) and washed with 2.times.150 ml PBS/1% Triton X-100, followed by4.times.40 ml PBS. To cleave the p38 kinase from the GST-p38 fusionprotein, the glutathione-sepharose resin was resuspended in 6 ml PBScontaining 250 units thrombin protease (Pharmacia, specificactivity >7500 units/mg) and mixed gently for 4 hours at roomtemperature. The glutathione-sepharose resin was removed bycentrifugation (600.times.g, 5 min) and washed 2.times.6 ml with PBS.The PBS wash fractions and digest supernatant containing p38 kinaseprotein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

The thrombin-cleaved p38 kinase was further purified by FPLC-anionexchange chromatography. Thrombin-cleaved sample was diluted 2-fold withBuffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5%glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchangecolumn equilibrated with Buffer A. The column was eluted with a 160 ml0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography

The concentrated Mono Q-p38 kinase purified sample was purified by gelfiltration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 columnequilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT,5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5ml/minute flowrate and protein was detected by absorbance at 280 nm.Fractions containing p38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at −80° C. Typical purifiedprotein yields from 5 L E. coli shake flasks fermentations were 35 mgp38 kinase.

In Vitro Assay

The ability of compounds to inhibit human p38 kinase alpha was evaluatedusing two in vitro assay methods. In the first method, activated humanp38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I(phosphorylated heat and acid stable protein-insulin inducible), in thepresence of gamma ³²P-ATP (³²P-ATP). PHAS-I was biotinylated prior tothe assay and provides a means of capturing the substrate, which isphosphorylated during the assay. p38 Kinase was activated by MKK6.Compounds were tested in 10 fold serial dilutions over the range of 100μM to 0.001 μM using 1% DMSO. Each concentration of inhibitor was testedin triplicate.

All reactions were carried out in 96 well polypropylene plates. Eachreaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and50 μM unlabeled ATP. Activation of p38 was required to achievesufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μgper 50 μl reaction volume, with a final concentration of 1.5 μM.Activated human p38 kinase alpha was used at 1 μg per 50 μl reactionvolume representing a final concentration of 0.3 μM. Gamma ³²P-ATP wasused to follow the phosphorylation of PHAS-I. ³²P-ATP has a specificactivity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reactionvolume. The reaction proceeded either for one hour or overnight at 30°C.

Following incubation, 20 μl of reaction mixture was transferred to ahigh capacity streptavidin coated filter plate (SAM-streptavidin-matrix,Promega) prewetted with phosphate buffered saline. The transferredreaction mix was allowed to contact the streptavidin membrane of thePromega plate for 1-2 minutes. Following capture of biotinylated PHAS-Iwith ³²P incorporated, each well was washed to remove unincorporated³²P-ATP three times with 2M NaCl, three washes of 2M NaCl with 1%phosphoric, three washes of distilled water and finally a single wash of95% ethanol. Filter plates were air-dried and 20 μl of scintillant wasadded. The plates were sealed and counted.

A second assay format was also employed that is based on p38 kinasealpha induced phosphorylation of EGFRP (epidermal growth factor receptorpeptide, a 21 mer) in the presence ³³P-ATP. Compounds were tested in 10fold serial dilutions over the range of 100 μM to 0.001 μM in 1% DMSO.Each concentration of inhibitor was tested in triplicate. Compounds wereevaluated in 50 μl reaction volumes in the presence of 25 mM Hepes pH7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin,0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05 μCi³³P-ATP. Reactions were initiated by addition of 0.09 μg of activated,purified human GST-p38 kinase alpha. Activation was carried out usingGST-MKK6 (5:1,p38:MKK6) for one hour at 30° C. in the presence of 50 μMATP. Following incubation for 60 minutes at room temperature, thereaction was stopped by addition of 150 μl of AG 1.times.8 resin in 900mM sodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer).The mixture was mixed three times with pipetting and the resin wasallowed to settle. A total of 50 μl of clarified solution head volumewas transferred from the reaction wells to Microlite-2 plates. 150 μl ofMicroscint 40 was then added to each well of the Microlite plate, andthe plate was sealed, mixed, and counted.

Representative compounds that exhibit IC₅₀ values between 1 and 25 μM(p38 alpha kinase assay) are: Example Nos. 20, 22, 23, 39, 43, 44, 48,50, 52, 53, 55, 57, 58, 62, 92, 115, 118, 136, 139, 141, 142, 149, 156,157, 169, 174, 219, 220, 244, 245, 387, 288, 289, 291, 292, 293, 294,295, 296, 298, 297, 300, 301, 302 304, 305, 309, 310, 311, 323, 360,394, 403, 414, 415, 416, 418, 420, 444, 447, 449, 451, 452, 471, 485,486, 496, 498, 499, 503, 506, 561, 569, 574, 575 and 576.

Representative compounds that exhibit IC₅₀ values between 25 and 100 μM(p38 alpha kinase assay) are: Example Nos. 1, 25, 33, 35, 37, 42, 45,47, 49, 119, 204, 308, 558, 560, 564, 565, 566, 568 and 577.

Representative compounds that exhibit IC₅₀ values less than 1 μM (p38alpha kinase assay) are: Example Nos. 6, 14, 8, 17, 10, 15, 4, 117, 161,162, 165, 170, 171, 172, 173 176, 179, 217, 218, 219, 220, 221, 223,225, 230, 231, 234, 235, 272, 273, 275, 276, 278, 280, 282, 286, 285,290, 312, 313, 314, 315, 316, 317, 318, 320, 321, 322, 364, 366, 400,402, 405, 421, 422, 423, 446, 448, 450, 458, 466, 467, 468, 469, 470,481, 482, 483, 484, 487, 489, 492, 493, 494, 495, 504, 521, 522, 523557, 587, 589, 590, 591, 597, 609, 610, 613, 629, 642, and 643.

Representative compounds that exhibit IC₅₀ values greater than 100 μM(p38 alpha kinase assay) are: Example Nos. 3, 11, 38, 56, 116, 121, 237,236, 413, 497 and 578.

TNF Cell Assays

Method of Isolation of Human Peripheral Blood Mononuclear Cells:

Human whole blood was collected in Vacutainer tubes containing EDTA asan anticoagulant. A blood sample (7 ml) was carefully layered over 5 mlPMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottomcentrifuge tube. The sample was centrifuged at 450-500.times.g for 30-35minutes in a swing out rotor at room temperature. After centrifugation,the top band of cells were removed and washed 3 times with PBS w/ocalcium or magnesium. The cells were centrifuged at 400.times.9 for 10minutes at room temperature. The cells were resuspended in MacrophageSerum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml.

LPS Stimulation of Human PBMs

PBM cells (0.1 ml, 2 million/ml) were co-incubated with 0.1 ml compound(10-0.41 μM, final concentration) for 1 hour in flat bottom 96 wellmicrotiter plates. Compounds were dissolved in DMSO initially anddiluted in TCM for a final concentration of 0.1% DMSO. LPS (Calbiochem,20 ng/ml, final concentration) was then added at a volume of 0.010 ml.Cultures were incubated overnight at 37° C. Supernatants were thenremoved and tested by ELISA for TNF-a and IL-b. Viability was analyzedusing MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS wasadded to remaining 0.1 ml cells. The cells were incubated at 37° C. for2-4 hours, then the O.D. was measured at 490-650 nM.

Maintenance and Differentiation of the U937 Human Histiocytic LymphomaCell Line

U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetalbovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2 mMglutamine (Gibco). Fifty million cells in 100 ml media were induced toterminal monocytic differentiation by 24 hour incubation with 20 ng/mlphorbol 12-myristate 13-acetate (Sigma). The cells were washed bycentrifugation (200.times.g for 5 min) and resuspended in 100 ml freshmedium. After 24-48 hours, the cells were harvested, centrifuged, andresuspended in culture medium at 2 million cells/ml.

LPS Stimulation of TNF Production by U937 Cells

U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound(0.004-50 μM, final concentration) for 1 hour in 96 well microtiterplates. Compounds were prepared as 10 mM stock solutions in DMSO anddiluted in culture medium to yield a final DMSO concentration of 0.1% inthe cell assay. LPS (E coli, 100 ng/ml final concentration) was thenadded at a volume of 0.02 ml. After 4 hour incubation at 37° C., theamount of TNF-.alpha. released in the culture medium was quantitated byELISA. Inhibitory potency is expressed as IC50 (μM).

Rat Assay

The efficacy of the novel compounds in blocking the production of TNFalso was evaluated using a model based on rats challenged with LPS. MaleHarlen Lewis rats [Sprague Dawley Co.] were used in this model. Each ratweighed approximately 300 g and was fasted overnight prior to testing.Compound administration was typically by oral gavage (althoughintraperitoneal, subcutaneous and intravenous administration were alsoused in a few instances) 1 to 24 hours prior to the LPS challenge. Ratswere administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.]intravenously via the tail vein. Blood was collected via heart puncture1 hour after the LPS challenge. Serum samples were stored at −20° C.until quantitative analysis of TNF-alpha. by EnzymeLinked-Immuno-Sorbent Assay (“ELISA”) [Biosource]. Additional details ofthe assay are set forth in Perretti, M., et al., Br. J. Pharmacol.(1993), 110, 868-874, which is incorporated by reference in thisapplication.

Mouse Assay

Mouse Model of LPS-Induced TNF Alpha Production

TNF alpha was induced in 10-12 week old BALB/c female mice by tail veininjection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 mlsaline. One hour later mice were bled from the retroorbital sinus andTNF concentrations in serum from clotted blood were quantified by ELISA.Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour afterLPS injection.

The compounds tested were administered to fasted mice by oral gavage asa suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 inwater at 1 hour or 6 hours prior to LPS injection. The 1 hour protocolallowed evaluation of compound potency at Cmax plasma levels whereas the6 hour protocol allowed estimation of compound duration of action.Efficacy was determined at each time point as percent inhibition ofserum TNF levels relative to LPS injected mice that received vehicleonly.

Induction and Assessment of Collagen-Induced Arthritis in Mice

Arthritis was induced in mice according to the procedure set forth in J.M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199(1984), which is incorporated herein by reference. Specifically,arthritis was induced in 8-12 week old DBA/1 male mice by injection of50 μg of chick type II collagen (CII) (provided by Dr. Marie Griffiths,Univ. of Utah, Salt Lake City, Utah) in complete Freund's adjuvant(Sigma) on day 0 at the base of the tail. Injection volume was 100 μl.Animals were boosted on day 21 with 50 μg of CII in incomplete Freund'sadjuvant (100 μl volume). Animals were evaluated several times each weekfor signs of arthritis. Any animal with paw redness or swelling wascounted as arthritic. Scoring of arthritic paws was conducted inaccordance with the procedure set forth in Wooley et al., GeneticControl of Type II Collagen Induced Arthritis in Mice: FactorsInfluencing Disease Suspectibility and Evidence for Multiple MHCAssociated Gene Control., Trans. Proc., 15:180 (1983). Scoring ofseverity was carried out using a score of 1-3 for each paw (maximalscore of 12/mouse). Animals displaying any redness or swelling of digitsor the paw were scored as 1. Gross swelling of the whole paw ordeformity was scored as 2. Ankylosis of joints was scored as 3. Animalswere evaluated for 8 weeks. 8-10 animals per group were used.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl,alkoxy, alkoxyalkyl, haloalkyl or carboxyl; wherein the alkyl portion ofthe alkyl, hydroxyalkyl, dihydroxyalkyl, alkanoyl, alkoxy, andalkoxyalkyl groups is unsubstituted or substituted with 1, 2, or 3groups that are independently halogen, C₁-C₄ alkoxy, C₁-C₄alkoxycarbonyl, or cyclopropyl; R₂ is arylalkoxy, optionally substitutedwith 1, 2, 3, 4, or 5 groups that are independently halogen, —NR₆R₇,haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl,—(C₁-C₄)alkyl-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —(C₁-C₄alkyl)-NRC(O)NR₁₆R₁₇, CN, hydroxyalkyl, dihydroxyalkyl, —OC(O)NR₆R₇, or—(C₁-C₆)alkyl-N(R)—CO₂R₃₀, wherein R₁₆ and R₁₇ are independently H orC₁-C₆ alkyl; or R₁₆, R₁₇ and the nitrogen to which they are attachedform a morpholinyl ring; R₆ and R₇ are independently at each occurrenceH, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl,arylalkyl, arylalkoxy, arylalkoxycarbonyl, or arylalkanoyl, wherein eachof the above is unsubstituted or substituted with 1, 2, or 3 groups thatare independently, halogen, alkoxy, alkyl, OH, SH, carboxaldehyde,haloalkyl, or haloalkoxy; or R₆, R₇, and the nitrogen to which they areattached form a morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinylring which is optionally substituted with 1 or 2 groups that areindependently C₁-C₄ alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,dihydroxyalkyl, or halogen; n is 0, 1, 2, 3, 4, 5 or 6; R at eachoccurrence is independently H or C₁-C₆ alkyl optionally substituted with1 or 2 groups that are independently OH, SH, halogen, amino,monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl; R₃₀ is C₁-C₆ alkyloptionally substituted with 1 or 2 groups that are independently OH, SH,halogen, amino, monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl; R₄ isalkyl optionally substituted with one or two groups that areindependently CO₂R, —CO₂alkyl, —C(O)NR₆R₇, —C(O)R₆, —N(R₃₀)C(O)NR₁₆R₁₇,—N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, arylalkoxy, heteroaryl, arylalkyl,hydroxyalkyl, dihydroxyalkyl, haloalkyl, —NR₆R₇, —C(O)NR₆R₇, alkoxy,alkoxyalkyl, or alkoxyalkoxy, wherein the heteroaryl or aryl portions ofthe above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groupsthat are independently halogen, hydroxy, alkoxy, alkyl,—CO₂—(C₁-C₆)alkyl, —CONR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆)alkyl-, nitro,haloalkyl, or haloalkoxy; and R₅ is arylalkyl or aryl wherein each ofthe above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groupsthat are independently alkyl, halogen, alkoxy, arylalkoxy, hydroxyalkyl,dihydroxyalkyl, thioalkoxy, —SO₂alkyl, alkoxycarbonyl,arylalkoxycarbonyl, CO₂R, CN, OH, amidinooxime, NR₈R₉, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, amidino, hydroxyalkyl, dihydroxyalkyl,carboxaldehyde, —NR₆R₇, haloalkyl, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —(C₁-C₄alkyl)-CO₂R, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-CN,—(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O—, —O—CH₂CH₂—O—, phenyl orhaloalkoxy; R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;R₉ is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl.
 2. A compoundaccording to claim 1 wherein R₁ is H, halogen, alkyl, hydroxyalkyl,dihydroxyalkyl, CN, alkoxy, C₂-C₄ alkynyl, C₂-C₆ alkenyl, alkoxyalkyl orhaloalkyl; wherein the alkyl groups are unsubstituted or substitutedwith 1, 2, or 3 groups that are independently halogen, methoxy, orethoxy; R₂ is phenyl(C₁-C₆)alkoxy optionally substituted with 1, 2, 3,4, or 5 groups that are independently halogen, NR₆R₇, haloalkyl,haloalkoxy, hydroxyalkyl, dihydroxyalkyl, alkyl, phenyl, pyridyl,piperidinyl, piperazinyl, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, —(C₁-C₄alkyl)-NRC(O)NR₁₆R₁₇, or —OC(O)NR₆R₇, wherein R₆ and R₇ areindependently at each occurrence H, alkyl, (C₁-C₄) hydroxyalkyl, (C₁-C₄)dihydroxyalkyl, (C₁-C₄)alkoxy, (C₁-C₄) alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, phenyl(C₁-C₄)alkyl, phenyl(C₁-C₄)alkoxy,phenyl(C₁-C₄)alkoxycarbonyl, or phenyl (C₁-C₄) alkanoyl, wherein each ofthe above is unsubstituted or substituted with 1, 2, or 3 groups thatare independently, halogen, OH, SH, C₃-C₆ cycloalkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, CF₃, carboxaldehyde, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, OCF₃; or R₆, R₇, and the nitrogen to whichthey are attached form a morpholinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1or 2 groups that are independently C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄alkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxycarbonyl, or halogen; and R₄ isalkyl optionally substituted with one or two groups that areindependently CO₂R, —CO₂alkyl, —C(O)NR₆R₇, —C(O)R₆, —N(R₃₀)C(O)NR₁₆R₁₇,—N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, —C(O)NR₆R₇, phenyl(C₁-C₆)alkoxy,phenyl(C₁-C₆)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy,alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, hydroxy, alkoxy, alkyl, nitro, CF₃, OCF₃; R₅ isphenyl(C₁-C₆)alkyl or phenyl wherein each of the above is unsubstitutedor substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkyl, halogen, C₁-C₆ alkoxy, phenyl C₁-C₆ alkoxy, C₁-C₆ thioalkoxy,C₁-C₆ alkoxycarbonyl, CO₂R, CN, —SO₂(C₁-C₆)alkyl, amidinooxime, NR₈R₉,—NR₆R₇, NR₆R₇C₁-C₆ alkyl, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, amidino,C₁-C₄ haloalkyl, hydroxy C₁-C₆ alkyl, C₁-C₆ dihydroxyalkyl, or C₁-C₄haloalkoxy; wherein R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenylC₁-C₆ alkyl and phenyl C₁-C₆ alkanoyl; and R₉ is aminoalkyl, mono C₁-C₆alkylamino C₁-C₆ alkyl, di C₁-C₆ alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl,C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl, indazolyl, and phenyl C₁-C₆alkanoyl.
 3. A compound according to claim 2, wherein R₁ is H, halogen,or C₁-C₄ alkyl, R₂ is benzyloxy optionally substituted with 1, 2, 3, 4,or 5 groups that are independently halogen, —(C₁-C₆)alkyl-N(R)—CO₂R₃₀,NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, (C₁-C₄) haloalkyl, —C(O)NR₆R₇, —(C₁-C₄alkyl)-NRC(O)NR₁₆R₁₇, (C₁-C₄)haloalkoxy, hydroxyalkyl, C₁-C₆dihydroxyalkyl, (C₁-C₆)alkyl, pyridyl, or R₆R₇N—(C₁-C₆ alkyl)-.
 4. Acompound according to claim 3, wherein R₅ is phenyl orphenyl(C₁-C₆)alkyl; wherein each of the above is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 groups that are independently alkyl,halogen, alkoxy, benzyloxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy,—CO₂(C₁-C₅ alkyl), CO₂R, CN, amidinooxime, —NR₈R₉, —NR₆R₇, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, amidino, CF₃, or OCF₃; R₈is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₆ alkyl and phenylC₁-C₆ alkanoyl; and R₉ is aminoalkyl, mono C₁-C₆ alkylamino C₁-C₆ alkyl,di C₁-C₆ alkylamino C₁-C₆ alkyl, C₁-C₆ alkyl, C₁-C₆ alkanoyl, phenylC₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄ alkanoyl.
 5. A compoundaccording to claim 3, wherein R₅ is phenyl, phenyl(C₁-C₆)alkyl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —CO₂(C₁-C₅alkyl), CO₂R, CN, amidinooxime, —NR₈R₉, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,—C(O)NR₆R₇, —(C₁-C₄)—C(O)NR₆R₇, amidino, CF₃, or OCF₃; wherein R₆ and R₇are independently at each occurrence H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ dihydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₄alkanoyl, phenyl C₁-C₄ alkyl, phenyl C₁-C₄ alkoxy, or phenyl C₁-C₄alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3groups that are independently, halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ alkyl, CF₃, or OCF₃; or R₆, R₇, and the nitrogen to whichthey are attached form a morpholinyl, thiomorpholinyl, or piperazinylring which is optionally substituted with 1 or 2 groups that areindependently C₁-C₄ alkyl, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄dihydroxyalkyl, or halogen; R₈ is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkanoyl,phenyl C₁-C₆ alkyl and phenyl C₁-C₆ alkanoyl; and R₉ is aminoalkyl, monoC₁-C₆ alkylamino C₁-C₆ alkyl, di C₁-C₆ alkylamino C₁-C₆ alkyl, C₁-C₆alkyl, C₁-C₆ alkanoyl, phenyl C₁-C₄ alkyl, indazolyl, and phenyl C₁-C₄alkanoyl.
 6. A compound according to claim 5, wherein R₅ is phenyl,benzyl or phenethyl, wherein each is optionally substituted with 1, 2,3, 4, or 5 groups that are independently C₁-C₆ alkyl, —NR₆R₇,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₈R₉, halogen, C₁-C₆ alkoxy,CO₂R, —(C₁-C₄ alkyl)-CO₂R, C₁-C₆ thioalkoxy, amidinooxime, C₁-C₆alkoxycarbonyl, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, C₁-C₆ hydroxyalkyl,C₁-C₆ dihydroxyalkyl, —(C₁-C₄ alkyl)-CN, CN, phenyl C₁-C₆ alkoxy, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, R₆R₇N—(C₁-C₆ alkyl)-, —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈, amidinooxime, —SO₂(C₁-C₆ alkyl), —O—CH₂—O—,—O—CH₂CH₂—O—, phenyl C₁-C₄ alkoxy, or phenyl; wherein R and R₇ areindependently at each occurrence H, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ dihydroxyalkyl, C₁-C₄ alkanoyl, or C₁-C₄ alkoxy, each of which isoptionally substituted with 1, 2, or 3 groups that are independentlyhalogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃,or OCF₃.
 7. A compound according to claim 6, wherein R₅ is phenyl,benzyl or phenethyl, each of which is unsubstituted or substituted with1, 2, 3, 4, or 5 groups that are independently CN, halogen, C₁-C₄alkoxy, CF₃, OCF₃, C₁-C₄ alkyl, —NR₈R₉, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, or—C(O)NR₆R₇, wherein R₆ and R₇ are independently at each occurrence H,C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₄ alkanoyl,or C₁-C₄ alkoxy, each of which is optionally substituted with 1, 2, or 3groups that are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.
 8. A compound according to claim3, wherein the R₅ group is of the formula:

wherein Z₁ and Z₂ are independently H, halogen, C₁-C₄ alkyl, or CO₂R;and Z is —C(O)NR₆R₇, —(C₁-C₄)alkyl-C(O)NR₆R₇, —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —NR₈R₉, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkyl, CO₂R, or halogen;wherein R₆ and R₇ at each occurrence are independently H, OH, C₁-C₆alkyl, amino C₁-C₄ alkyl, NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆alkyl)C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆alkoxy C₁-C₆ alkyl, or —SO₂(C₁-C₆ alkyl) each of which is optionallysubstituted with 1, 2, or 3 groups that are independently halogen, OH,SH, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃; orR₆, R₇, and the nitrogen to which they are attached form a piperidinyl,pyrrolidinyl, piperazinyl, or a morpholinyl, thiomorpholinyl, ringoptionally substituted with 1 or 2 groups that are independently alkyl,hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen; and R₁₈is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆ alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₄ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.
 9. Acompound according to claim 3, wherein R₅ is phenyl, which is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl),C₁-C₆ hydroxyalkyl, dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH,C₁-C₆ alkoxycarbonyl, CF₃, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₈R₁₇, —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈; wherein R₁₅ is H or C₁-C₆ alkyl; R₁₆ and R₁₇ areindependently H or C₁-C₆ alkyl; or R₁₆, R₁₇, and the nitrogen to whichthey are attached form a morpholinyl ring; and R₁₈ is C₁-C₆ alkyloptionally substituted with —O—(C₂-C₆ alkanoyl, C₁-C₆ hydroxyalkyl,C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl; aminoC₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.
 10. A compound accordingto claim 9, wherein R₅ is of the formula:

Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄ alkyl,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH,C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl; Z₃ is H, C₁-C₄ alkyl,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH,C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl; wherein R₆ and R₇ at eachoccurrence are independently H, OH, C₁-C₆ alkyl, amino C₁-C₄ alkyl,NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl),or C₁-C₆ alkanoyl, each of which is optionally substituted with 1, 2, or3 groups that are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.
 11. A compound according to claim10, wherein R₅ is of the formula:

wherein Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl),C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R,OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl; Z₃ is H, C₁-C₄ alkyl,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH,C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl, wherein R₆ and R₇ at eachoccurrence are independently H, OH, C₁-C₆ alkyl, amino C₁-C₄ alkyl,NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl),or C₁-C₆ alkanoyl, each of which is optionally substituted with 1, 2, or3 groups that are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.
 12. A compound according to claim10, wherein R₅ is of the formula:

wherein Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl),C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R,OH, C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl; Z₃ is H, C₁-C₄ alkyl,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, OH,C₁-C₆ alkoxycarbonyl, or C₁-C₄ haloalkyl, wherein R₆ and R₇ at eachoccurrence are independently H, OH, C₁-C₆ alkyl, amino C₁-C₄ alkyl,NH(C₁-C₆ alkyl)alkyl, N(C₁-C₆ alkyl)(C₁-C₆ alkyl)C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, —SO₂(C₁-C₆alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl),or C₁-C₆ alkanoyl, each of which is optionally substituted with 1, 2, or3 groups that are independently halogen, OH, SH, C₃-C₆ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ alkyl, OH, CF₃, or OCF₃.
 13. A compound according to claim9, wherein R₅ is either

wherein Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl),C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R,C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈; Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl,—(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈; R₆, R₇,and the nitrogen to which they are attached form a piperidinyl,pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substitutedwith 1 or 2 groups that are independently alkyl, hydroxy, hydroxy C₁-C₄alkyl, C₁-C₄ dihydroxyalkyl, or halogen; R₁₅ is H or C₁-C₆ alkyl; R₁₆and R₁₇ are independently H or C₁-C₆ alkyl; or R₁₆, R₁₇, and thenitrogen to which they are attached form a morpholinyl ring; R₁₈ isC₁-C₆ alkyl optionally substituted with —O—(C₂-C₆ alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.
 14. Acompound according to claim 13, wherein R₅ is of the formula:

Z₁ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄ alkyl,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆alkoxycarbonyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈; Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl,—(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈; R₆, R₇,and the nitrogen to which they are attached form a piperidinyl,pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substitutedwith 1 or 2 groups that are independently alkyl, hydroxy, hydroxy C₁-C₄alkyl, C₁-C₄ dihydroxyalkyl, or halogen; R₁₅ is H or C₁-C₆ alkyl; R₁₆and R₁₇ are independently H or C₁-C₆ alkyl; or R₁₆, R₁₇, and thenitrogen to which they are attached form a morpholinyl ring; R₁₈ isC₁-C₆ alkyl optionally substituted with —O—(C₂-C₆ alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.
 15. Acompound according to claim 13, wherein R₅ is of the formula:

wherein Z₁ is H, halogen, C₁-C₄ alkyl C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ dihydroxyalkyl, or C₁-C₄ alkoxy; and Z₂ is C₁-C₄alkyl, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl),C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R,C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄alkyl)-NR₁₅C(O)R₁₈; Z₃ is H, C₁-C₄ alkyl, —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, —NR₆R₇, NR₆R₇(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl, C₁-C₆dihydroxyalkyl, halogen, C₁-C₄ alkoxy, CO₂R, C₁-C₆ alkoxycarbonyl,—(C₁-C₄ alkyl)-NR₁₅C(O)NR₁₆R₁₇, or —(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈; R₆, R₇,and the nitrogen to which they are attached form a piperidinyl,pyrrolidinyl, piperazinyl, or a morpholinyl ring, each of which isoptionally substituted with 1 or 2 groups that are independently alkyl,hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen; R₁₅ is Hor C₁-C₆ alkyl; R₁₆ and R₁₇ are independently H or C₁-C₆ alkyl; or R₁₆,R₁₇, and the nitrogen to which they are attached form a morpholinylring; R₁₈ is C₁-C₆ alkyl optionally substituted with —O—(C₂-C₆ alkanoyl,C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyC₁-C₆ alkyl; amino C₁-C₆ alkyl, mono or dialkylamino C₁-C₆ alkyl.
 16. Acompound of the formula

or a pharmaceutically acceptable salt thereof, wherein L is —O—; M is—CH₂—; X₁ is selected from —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, OH, halogen, haloalkyl,alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C₃-C₇ cycloalkyl,R₆R₇N—(C₁-C₆ alkyl)-, —CO₂—C₁-C₆)alkyl, —N(R)C(O)NR₆R₇,—N(R)C(O)—(C₁-C₆)alkoxy, CO₉R—(C₁-C₆ alkyl)-, or —SO₂NR₆R₇; wherein theheteroaryl and heterocycloalkyl groups are optionally substituted with—NR₆R₇, —C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhalogen; R₅ is

wherein X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) are independentlyselected from —C(O)NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —NR₆R₇,hydroxy(C₁-C₄)alkyl, C₁-C₄ dihydroxyalkyl, H, OH, halogen, haloalkyl,alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C₃-C₇ cycloalkyl,R₆R₇N—(C₁-C₆ alkyl)-, —CO₂—(C₁-C₆)alkyl, —N(R)C(O)NR₆R₇,—N(R)C(O)—(C₁-C₆)alkoxy, CO₂R—(C₁-C₆ alkyl)-, or —SO₂NR₆R₇; wherein theheteroaryl and heterocycloalkyl groups are optionally substituted with—NR₆R₇, —C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhalogen; and Y, Y₁, Y₂, Y₃, and Y₄ are independently selected from H,halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl,alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, and carboxyl. 17.A compound according to claim 16, wherein Y₂, Y₄, and Y areindependently halogen; and Y₁ and Y₃ are both hydrogen.
 18. A compoundaccording to claim 17, wherein

R₅ is X₁ is methyl, NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl, or—(C₁-C₄ alkyl)-morpholinyl; X₂ is H, methyl, NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, C₁-C₆ hydroxyalkyl,C₁-C₆ dihydroxyalkyl, or —(C₁-C₄ alkyl)-morpholinyl; and X_(a) and X_(e)are independently halogen, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆alkyl), methyl, or hydrogen.
 19. A compound according to claim 18,wherein one of X_(b) and X_(c) is hydrogen and the other is —NR₆R₇,R₆R₇N—(C₁-C₆ alkyl)-, —C(O)NR₆R₇, —SO₂NR₆R₇, or halogen; where R₆ and R₇are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₈ alkoxy, C₁-C₆alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, OH, C₁-C₆ hydroxyalkyl, C₁-C₆dihydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, whereineach of the above is unsubstituted or substituted with 1, 2, or 3 groupsthat are independently, halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,piperidinyl C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆alkyl, OH, SH, NH₂, NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄alkyl, CF₃, or OCF₃; or R₆, R₇, and the nitrogen to which they areattached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl,or piperazinyl ring which is optionally substituted with 1 or 2 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄alkyl, C₁-C₄ dihydroxyalkyl, or halogen.
 20. A compound according toclaim 19, wherein R₆ and R₇ are independently at each occurrence H,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, OH, C₁-C₆ hydroxyalkyl, C₁-C₆ dihydroxyalkyl,—(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, benzyl,phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, wherein each of the aboveis unsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinylC₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, NH₂,NH(alkyl), N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, orOCF₃.
 21. A compound according to claim 19, wherein X_(c) is —C(O)NR₆R₇,—(C₁-C₆ alkyl)-C(O)NR₆R₇, —NR₆R₇, or R₆R₇N—(C₁-C₆ alkyl)-; wherein R₆and R₇ are independently at each occurrence H, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, OH, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, C₁-C₆ dihydroxyalkyl,—(C₁-C₄)alkyl-CO₂-alkyl, pyridyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, benzyl,phenyl C₁-C₆ alkoxy, or phenyl C₁-C₆ alkanoyl, wherein each of the aboveis unsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinylC₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, —NH₂,—NH(alkyl), —N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, orOCF₃; or R₆, R₇, and the nitrogen to which they are attached form amorpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinylring which is optionally substituted with 1 or 2 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl,C₁-C₄ dihydroxyalkyl, or halogen.
 22. A compound according to claim 21,wherein R₆ is hydrogen; and R₇ is C₁-C₆ alkyl or C₁-C₆ alkanoyl, each ofwhich is optionally substituted with 1, 2, or 3 groups that areindependently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), OH, SH,cyclopropyl, or C₁-C₄ alkoxy.
 23. A compound according to claim 22,wherein X_(c) is —C(O)NR₆R₇.
 24. A compound according to claim 22,wherein X_(c) is NR₆R₇, or R₆R₇N—(C₁-C₆ alkyl)-.
 25. A compoundaccording to claim 16, wherein X_(a) is hydrogen; two of X_(b), X_(c),and X_(d) are hydrogen and the other is —C(O)NR₆R₇, —(C₁-C₆alkyl)-C(O)NR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)- or —CO₂—(C₁-C₆)alkyl;wherein R₆ and R₇ are independently at each occurrence H, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, OH, C₁-C₆hydroxyalkyl, C₁-C₆ dihydroxyalkyl, —(C₁-C₄)alkyl-CO₂-alkyl, pyridylC₁-C₆ alkyl, C₁-C₆ alkanoyl, benzyl, phenyl C₁-C₆ alkoxy, or phenylC₁-C₆ alkanoyl, wherein each of the above is unsubstituted orsubstituted with 1, 2, or 3 groups that are independently, halogen,C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, piperidinyl C₁-C₆ alkyl, morpholinylC₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, OH, NH₂, NH(alkyl),N(alkyl)(alkyl), —O—C₁-C₄ alkanoyl, C₁-C₄ alkyl, CF₃, or OCF₃; or R₆,R₇, and the nitrogen to which they are attached form a morpholinyl,piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionallysubstituted with 1 or 2 groups that are independently C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl, or halogen;and X_(e) is hydrogen, methyl, C₁-C₂ alkoxy, or halogen.
 26. A compoundaccording to claim 25, wherein X_(b) is —C(O)NR₆R₇—(C₁-C₆alkyl)-C(O)NR₆R₇, —NR₆R₇, or R₆R₇N—(C₁-C₆ alkyl)- wherein R₆ is hydrogenor C₁-C₄ alkyl; R₇ is OH, C₁-C₆ alkyl or C₁-C₆ alkanoyl, wherein thealkyl and alkanoyl groups substituted with 1, 2, or 3 groups that areindependently NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), C₃-C₆cycloalkyl, OH, or C₁-C₄ alkoxy.
 27. A compound according to claim 16,wherein X_(a) is halogen or methyl; X_(b) is H, —NR₆R₇, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, or —CO₂—(C₁-C₆)alkyl; X_(c) is —NR₆R₇, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, halogen, —CO₂—(C₁-C₆)alkyl, NH₂, NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)(C₁-C₆ alkyl), or piperazinyl, wherein the piperazinyl group isoptionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, hydroxy C₁-C₄ alkyl, C₁-C₄ dihydroxyalkyl,or halogen; X_(d) is hydrogen; X_(e) is H, methyl, NH₂, NH(C₁-C₆ alkyl)or N(C₁-C₆ alkyl)(C₁-C₆ alkyl).
 28. A compound according to claim 16,wherein X₁ is selected from OH, halogen, CF₃, alkyl, OCF₃, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,piperidinyl, piperazinyl, or C₃-C₇ cycloalkyl, wherein each of the aboveis optionally substituted with —NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R_(7, R) ₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy,or halogen; and X₂, X_(a), X_(b), X_(c), X_(d), and X_(e) areindependently selected from H, OH, halogen, CF₃, alkyl, OCF₃, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,piperidinyl, piperazinyl, or C₃-C₇ cycloalkyl, wherein each of the aboveis optionally substituted with —NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄alkyl)-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-, C₁-C₆ alkyl, C₁-C₆ alkoxy, orhalogen.
 29. A compound which is(+/−)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamideor a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprising a pharmaceutical acceptable carrier and acompound or salt according to claim
 1. 31. A method of treating asthmaand chronic pulmonary inflammatory disease in a subject, the methodcomprising treating a subject having or susceptible to such disorder orcondition with a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halogen,alkyl, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl,alkoxy, alkoxyalkyl, haloalkyl or carboxyl; wherein the alkyl portion ofthe alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl,alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstitutedor substituted with 1, 2, or 3 groups that are independently halogen,C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, or cyclopropyl; R₂ is arylalkoxyoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently halogen, —NR₆R₇, haloalkyl, haloalkoxy, alkyl, heteroaryl,heteroarylalkyl, —(C₁-C₄)alkyl-C(O)NR₆R₇, R₆R₇N—(C₁-C₆ alkyl)-,—C(O)NR₆R₇, —(C₁-C₄ alkyl)-NRC(O)NR₁₆R₁₇, CN, hydroxyalkyl,dihydroxyalkyl, —OC(O)NR₆R₇, or —(C₁-C₆)alkyl-N(R)—CO₂R₃₀, wherein R₁₆and R₁₇ are independently H or C₁-C₆ alkyl; or R₁₆, R₁₇ and the nitrogento which they are attached form a morpholinyl ring; R₆ and R₇ areindependently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl,alkoxy, alkoxyalkyl, alkanoyl, arylalkyl, arylalkoxy,arylalkoxycarbonyl, or arylalkanoyl, wherein each of the above isunsubstituted or substituted with 1, 2, or 3 groups that areindependently, halogen, alkoxy, alkyl, OH, SH, carboxaldehyde,haloalkyl, or haloalkoxy; or R₆, R₇, and the nitrogen to which they areattached form a morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinylring which is optionally substituted with 1 or 2 groups that areindependently C₁-C₄ alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,dihydroxyalkyl, or halogen; n is 0, 1, 2, 3, 4, 5 or 6; R at eachoccurrence is independently H or C₁-C₆ alkyl optionally substituted with1 or 2 groups that are independently OH, SH, halogen, amino,monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl; R₃₀ is C₁-C₆ alkyloptionally substituted with 1 or 2 groups that are independently OH, SH,halogen, amino, monoalkylamino, dialkylamino or C₃-C₆ cycloalkyl; R₄ isH, alkyl optionally substituted with one or two groups that areindependently CO₂R, —CO₂alkyl, —C(O)NR₆R₇, —C(O)R₆, —N(R₃₀)C(O)NR₁₆R₁₇,—N(R₃₀)C(O)—(C₁-C₆)alkoxy, or —NR₆R₇, arylalkoxy, heteroaryl, arylalkyl,hydroxyalkyl, dihydroxyalkyl, haloalkyl, —NR₆R₇, —C(O)NR₆R₇, alkoxy,alkoxyalkyl, or alkoxyalkoxy, wherein the heteroaryl or aryl portions ofthe above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groupsthat are independently halogen, hydroxy, alkoxy, alkyl,—CO₂—(C₁-C₆)alkyl, —CONR₆R₇, —NR₆R₇, R₆R₇N—(C₁-C₆)alkyl-, nitro,haloalkyl, or haloalkoxy; and R₅ is arylalkyl, aryl, heteroaryl,heteroarylalkyl, heterocycloalkylalkyl, or heterocycloalkyl; whereineach of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5groups that are independently alkyl, halogen, alkoxy, arylalkoxy,hydroxyalkyl, dihydroxyalkyl, thioalkoxy, —SO₂alkyl, alkoxycarbonyl,arylalkoxycarbonyl, CO₂R, CN, OH, amidinooxime, NR₈R₉, R₆R₇N—(C₁-C₆alkyl)-, —C(O)NR₆R₇, amidino, hydroxyalkyl, dihydroxyalkyl,carboxaldehyde, —NR₆R₇, haloalkyl, —(C₁-C₄ alkyl)-C(O)NR₆R₇, —(C₁-C₄alkyl)-CO₂R, —(C₁-C₄ alkyl)-C₁-C₆ alkoxycarbonyl, —(C₁-C₄ alkyl)-CN,—(C₁-C₄ alkyl)-NR₁₅C(O)R₁₈, —O—CH₂—O—, —O—CH₂CH₂—O—, phenyl orhaloalkoxy; R₈ is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;R₉ is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl.